Clinical trial NCT03364348
Conditions: HER2 Positive Breast Carcinoma Recurrent Breast Carcinoma Stage III Breast Cancer Stage IIIA Breast Cancer Stage IIIB Breast Cancer Stage IIIC Breast Cancer Stage IV Breast Cancer
Sponsor: George W. Sledge Jr.
Start date: 2017-10-30; Completion date: 2022-02-14
Enrollment: 18 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial studies the best dose and side effects of utomilumab (4-1BB agonist monoclonal antibody PF-05082566) with trastuzumab emtansine or trastuzumab in treating patients with HER2-positive breast cancer that has spread to other places in the body. Monoclonal antibodies, such as utomilumab, trastuzumab emtansine, and trastuzumab may interfere with the ability of tumor cells to grow and spread.

Detailed description:
PRIMARY OBJECTIVE:

Estimate the maximum tolerated dose (MTD) and determine the recommended dose (RP2D) of utomilumab in combination with ado-rastuzumab emtansine (T-DM1) or trastuzumab in subjects with HER2-positive advanced breast cancer.

SECONDARY OBJECTIVES:

* Determine the objective tumor response (ORR)
* Determine the time to tumor response (TTR)
* Determine the duration of response (DR)
* Determine progression free survival (PFS)
* Assess the safety and tolerability of utomilumab in combination with ado-trastuzumab emtansine or trastuzumab

OUTLINE: Patients are randomized to 1 of 2 cohorts.

COHORT 1: Dose 1: Utomilumab 20 mg IV + ado-trastuzumab emtansine (T-DM1) 3.6 mg/kg IV every 3 weeks. Dose 2: Dose Level 2 - Utomilumab 100 mg IV + ado-trastuzumab emtansine 3.6 mg/kg IV every 3 weeks

COHORT 2: Dose 1: Utomilumab 20 mg IV + trastuzumab 6 mg/kg IV every 3 weeks. Dose Level 2 - Utomilumab 100 mg IV + trastuzumab 6 mg/kg IV every 3 weeks.

Arms: arm 1: Utomilumab 20 mg IV + trastuzumab 6 mg/kg IV every 3 weeks. 3 subjects will be treated at this dose level. If no DLT events are recorded, then utomilumab dose will be increased to 100 mg (Dose Level 1B). arm 2: Utomilumab 100 mg IV + trastuzumab 6 mg/kg IV every 3 weeks. arm 3: Utomilumab 20 mg IV + ado-trastuzumab emtansine 3.6 mg/kg IV every 3 weeks. arm 4: Utomilumab 100 mg IV + ado-trastuzumab emtansine 3.6 mg/kg IV every 3 weeks.
Interventions: intervention 1: Utomilumab intervention 2: Trastuzumab intervention 3: Ado-Trastuzumab Emtansine
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
IRB-37299 
Page 1 of 87 
21 September 2020 
 
A Phase 1B Dose-escalation Trial of Human Anti-4-1BB Agonistic Antibody 
Utomilumab (PF-05082566) in Combination with  
Ado-trastuzumab Emtansine or Trastuzumab in Patients with  
HER2-postive Advanced Breast Cancer 
CONFIDENTIAL 
21 September 2020 
Protocol Director / Principal Investigator / IND-holder 
George W Sledge, Jr, MD,  Professor of Medicine 
Chief, Division of Oncology  
Stanford University School of Medicine, CCSR 1115  
69 Campus Drive West  
Stanford, CA  94305-5456 
Telephone: XXX-XXX-XXXX;  Fax: XXX-XXX-XXXX 
e-mail: gsledge@stanford.edu 
Biostatistician 
George W Sledge, Jr, MD 
(with support from the Stanford Cancer Institute biostatistics core service, and from Pfizer) 
IRB-37299  
BRS0070 
NCT03364348 
 


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Participating Investigators and Center: 
The participating Clinical Center is Stanford University, Stanford (USA). 
Details of the Principal Investigators, Sub-investigators, and other key study personnel are 
recorded on the Participating Investigators and Centers list Trial Master File. 
IND: 
IND 131822  
IRB number: 
IRB-37299  
Initial IRB approval: 
25 October 2016  
Initial SRC approval: 
25 May 2017  


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PROTOCOL VERSION AND AMENDMENT HISTORY: 
Protocol  
Amendment 
No. 
Date of Issue 
Reason for Protocol Amendment 
Amendment 1 
1 Nov 2016 
Incorporation of comments from FDA and Stanford Cancer Institute 
Scientific Peer Review Committee  
(See Appendix 8 Change Summary Tables) 
Amendment 2 16 Nov 2017 
 Objectives and Endpoints re-stated and re-organized to enable 
revised expression of ClinicalTrials.gov outcomes consistent with 
ClinicalTrials.gov requirements  
 Clarify duration of treatment 
Amendment 3 
11 Mar 2019 
1. The name used for study agent PF-05082566 is updated to 
utomilumab.  For ease of review, this is only tracked in 
presentations of the protocol title.  
2. Updates clinical experience and safety profile of utomilumab.  
3. Eligibility criteria and Eligibility Checklist harmonized to a single 
instance at Section 3.1.  Note:  the move of the checklist is not 
tracked in track document, changes to the eligibility are tracked.  
4. Eligibility criteria are simplified and edited for clarity, and revised 
to improve eligibility of appropriate candidate subjects 
5. Clarifies that cohort accrual, ie, to utomilumab in combination 
with ado-trastuzumab emtansine (T-DM1) or trastuzumab, will be 
in parallel.   
6. The sample size has been decreased to not exceed the first step of 
the Simon two-step study design.  
7. References to the sponsor-investigator, other investigators, and the 
utomilumab manufacturer have been aligned to those roles.  
8. Information regarding oversight of possible additional clinical 
sites has been added throughout.  
9. Performance windows defined for procedures. 
10. Collection of blood samples for pharmacokinetics harmonized to 
other procedures 
11. Treatment beyond 24 cycles (about 18 months) will be allowed by 
investigator discretion.  
12. Study identifiers, including NCT number, added to title page 
13. CTCAE reference updated to version 5 
14. Verbatim change summary table (Appendix 8 and 9) deleted. 
15. Other changes as indicated. 


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Amendment 4 
25 Jul 2019 
Clarifies/harmonizes the response evaluation criteria as the Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1 rather than 
immune-related RECIST. 
Removes reference to extended treatment after 24 cycles (te3xt for 
Study Schema), and clarifies rationale for continued dosing 
(Section 8.9). 
Clarifies Inclusion Criteria regarding prior treatment, for Cohort 1 
and 2 (Section 3, Inclusion Criteria 1) 
Removes unnecessary details in Exclusion Criteria regarding venous 
thromboembolism (Section 3, Exclusion Criteria 14) 
Harmonizes study schema at Figure 9 to correct version (see pg 12). 
Clarifies window for administration of ado-trastuzumab emtansine 
and trastuzumab (Section 5.5) 
Clarifies timing and requirements for tumor assessments 
(Section 5.5) 
Amendment 5 
6 Mar 2020 
 Makes the study a single-center study. 
 Close enrollment in Cohort 2 (utomilumab plus trastuzumab) with 
a total of 5 subjects enrolled. 
 For Cohort 1 (utomilumab plus ado-trastuzumab-emtansine), 
specify a maximum enrollment of 17 subjects to received 100 mg 
ado-trastuzumab-emtansine 
 Total protocol enrollment is up to 25 subjects 
 


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SIGNATURE PAGE 
SPONSOR-INVESTIGATOR SIGNATURE 
I have read and agree to the protocol, as detailed in this document.  I am aware of my 
responsibilities as an Investigator under the guidelines of Good Clinical Practice (GCP),1 the 
Declaration of Helsinki,2 the Code of Federal Regulations (CFR) Title 21,3 the applicable 
regulations of the relevant entities (Stanford University, Stanford Hospitals and Clinics), and the 
clinical trial protocol.  I agree to conduct the trial according to these regulations and guidelines 
and to appropriately direct and assist the staff under my control, who will be involved in the trial, 
and ensure that all staff members are aware of their clinical trial responsibilities. 
Investigator's Name:  
George W Sledge, Jr, MD 
Name of Site:  
Stanford Hospitals and Clinics, Stanford University 
Investigator's Signature:  
__________________________________________ 
 
1  
FDA Guidance for Industry: E6 Good Clinical Practice Guidelines, April 1996. 
2  
World Medical Association , Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Patients. 
3  
United States Code of Federal Regulations (CFR), Title 21, Food and Drugs. 


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TABLE OF CONTENTS 
Section 
 
Page Number 
Protocol Synopsis .............................................................................................................................7 
Study Schema ...................................................................................................................................13 
1.  
BACKGROUND .....................................................................................................................16 
1.1  4-1BB Target Biology and Mechanism of Action .......................................................16 
1.2. Preclinical Profiles of PF-05082566 ..............................................................................17 
1.2.1.  In vitro Data ........................................................................................................17 
1.2.2.  In vivo Data .........................................................................................................18 
1.2.3.  Clinical Experience ............................................................................................18 
1.3. Trastuzumab and Ado-Trastuzumab Emtansine .......................................................30 
1.4. Study Rationale ..............................................................................................................31 
1.4.1. Rationale for the Combination of Utomilumab with Ado-Trastuzumab 
and Trastuzumab ...............................................................................................31 
1.4.2.  Rationale for Utomilumab and Ado-Trastuzumab/Trastuzumab Doses .....34 
1.4.2.1.  Utomilumab ..........................................................................................34 
1.4.2.2.  Ado-Trastuzumab / Trastuzumab ......................................................36 
2.  
STUDY OBJECTIVES;   ENDPOINTS;  AND OUTCOMES ...........................................36 
2.1. Objectives........................................................................................................................36 
2.2. Endpoints ........................................................................................................................37 
2.3. ClinicalTrials.gov Outcomes .........................................................................................38 
3.  
PARTICIPANT SELECTION ..............................................................................................38 
3.1. Inclusion Criteria  ..........................................................................................................39 
3.2. Exclusion Criteria  .........................................................................................................42 
3.3. Informed Consent Process ............................................................................................45 
3.4. Study Timeline  ..............................................................................................................45 
4.  
STUDY DESIGN .....................................................................................................................45 
4.1. Starting Dose Selection Strategy...................................................................................45 
4.2. Criteria for Dose-Escalation .........................................................................................45 
4.3. Expansion Phase 1B Cohorts 1 and 2 ...........................................................................48 
4.4. Dose-limiting Toxicity (DLT) Definition ......................................................................48 
4.5. Maximum-tolerated Dose (MTD) Definition ...............................................................49 
4.6. Recommended Phase 2 Dose (RP2D) Definition .........................................................49 


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4.7. Concomitant Medication and Supportive Care Guidelines .......................................49 
4.8. Criteria for Removal From Study  ...............................................................................50 
4.9. Alternatives to study participation ...............................................................................51 
5.  
INVESTIGATIONAL AGENT INFORMATION ..............................................................51 
5.1  Physical, Chemical, and Pharmaceutical Properties and Formulation  ...................51 
5.2  Formulation of utomilumab Solution for Intravenous administration ....................51 
5.3  Agent Accountability .....................................................................................................51 
5.4  Drug Storage and Accountability .................................................................................52 
5.5  Drug Administration .....................................................................................................52 
6. 
DOSE MODIFICATIONS .....................................................................................................53 
7.  
ASSESSMENTS ......................................................................................................................56 
7.1  Safety Assessment ..........................................................................................................57 
7.1.1  Adverse Events ...................................................................................................57 
7.1.2  Laboratory Safety Assessments ........................................................................57 
7.1.3  Vital Signs and Physical Examination .............................................................57 
7.1.4  ECG Assessments ...............................................................................................58 
7.2  Tumor Response Assessments ......................................................................................58 
7.3  Pharmacokinetic Assessment ........................................................................................59 
7.4  Immunogenicity Assessment .........................................................................................59 
7.5  Pharmacodynamic Assessments ...................................................................................59 
7.5.1.   Blood for Immunomodulation/Cytokine Release Biomarkers ......................59 
7.5.2.   Pharmacodynamic Assessment of Lymphocyte Subpopulations ..................60 
7.5.3.   T-cell receptor assessment .................................................................................60 
7.6  Tumor Biopsies...............................................................................................................60 
8.  
ADVERSE EVENT REPORTING .......................................................................................60 
8.1  Reporting Period ............................................................................................................61 
8.2  Definition of an Adverse Event .....................................................................................61 
8.3  Abnormal Test Findings ................................................................................................62 
8.4  Serious Adverse Events .................................................................................................62 
8.5  Causality Assessment .....................................................................................................62 
8.6  Risks Associated with Trastuzumab ............................................................................63 
8.7  Risks Associated with Ado-Trastuzumab Emtansine  ................................................64 
8.8  Infusion-Related Symptoms with Hypersensitivity Reactions ...................................65 


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8.9  Rationale for Continued Dosing ...................................................................................66 
9.  
CORRELATIVE/SPECIAL STUDIES ................................................................................66 
9.1  Biomarkers .....................................................................................................................66 
10.  REGULATORY CONSIDERATIONS ................................................................................66 
10.1  Institutional Review of Protocol ...................................................................................66 
10.2  Clinical Site Selection for Stanford Sponsored Clinical Investigation ......................67 
10.3  Site Communication.......................................................................................................68 
10.4  Subject Registration.......................................................................................................68 
10.5  Data and Safety Monitoring Plan .................................................................................69 
10.6  Data Management Plan .................................................................................................69 
10.7  Ethical Conduct of the Study ........................................................................................69 
11.  STUDY DISCONTINUATION CRITERIA ..........................................................................69 
12.  PUBLICATIONS BY INVESTIGATORS  ............................................................................70 
13.  DATA ANALYSIS/STATISTICAL METHODS ..................................................................70 
13.1 Analysis Sets ....................................................................................................................70 
13.2 Statistical Methods and Sample Size Determination ...................................................71 
13.3 Efficacy Analysis .............................................................................................................71 
13.4 Analysis of Pharmacokinetics and Pharmacodynamics ..............................................71 
13.4.1 Analysis of Pharmacokinetics of Study Drugs .................................................71 
13.4.2.  Analysis of Immunogenicity Data of Study Drugs .........................................72 
13.4.3.  Analysis of Biomarker Endpoints....................................................................72 
13.4.4.  Population Pharmacokinetic Analysis or Pharmacokinetic / 
Pharmacodynamic (PK/PD) Modeling ............................................................72 
13.5 Safety Analysis ................................................................................................................72 
13.5.1 Analysis of the Primary Endpoint .....................................................................72 
13.5.2 Analysis of Secondary Safety Endpoints ..........................................................72 
14.  REFERENCES ..........................................................................................................................74 
Appendix 1  Determination of Efficacy – Solid Tumors  .............................................................76 
Appendix 2  ECOG Performance Status .......................................................................................80 
Appendix 3  Schedule of Activities  ..............................................................................................81 
Appendix 4  Tumor Biopsy Recommendations  ............................................................................85 
Appendix 5  Correlative / Special Studies – Biomarkers  ............................................................87 
Appendix 6  List of Abbreviations ..................................................................................................88 


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1.  PROTOCOL SYNOPSIS 
 
FULL TITLE 
A Phase 1B Dose Escalation Trial of human anti-4-1BB 
agonistic antibody utomilumab (PF-05082566) in combination 
with ado-trastuzumab-emtansine or trastuzumab in patients 
with HER2-positive advanced breast cancer 
SHORT TITLE 
Phase 1B Trial of Utomilumab (PF-05082566) in Combination 
with Ado-trastuzumab emtansine or Trastuzumab in HER2-positive 
Advanced Breast Cancer  
STUDY PHASE 
1B 
INVESTIGATIONAL 
PRODUCT 
Fully human anti-4-1BB agonistic antibody utomilumab 
PRIMARY 
OBJECTIVES 
Estimate the maximum-tolerated dose (MTD) and determine the 
recommended phase 2 dose (RP2D) of utomilumab in combination 
with ado-trastuzumab emtansine (T-DM1) in subjects with 
HER2-positive advanced breast cancer. 
SECONDARY 
OBJECTIVES 
1) Determine the objective tumor response rate (ORR) 
2) Determine the time-to-tumor response (TTR) 
3) Determine the duration of response (DR) 
4) Determine progression-free survival (PFS)  
5) Assess the safety and tolerability of utomilumab in combination 
with ado-trastuzumab emtansine or trastuzumab 
EXPORATORY 
OBJECTIVES 
1) Evaluate the pharmacokinetics (PK) of utomilumab and 
ado-trastuzumab emtansine or trastuzumab when given in 
combination 
2) Evaluate the immunogenicity of utomilumab and 
ado-trastuzumab emtansine or trastuzumab when given in 
combination 
3) Assess the presence of CD8+ T-cells in HER2-positive tumors  
4) To evaluate the modulation of immune activity biomarkers by 
utomilumab in combination with ado-trastuzumab emtansine or 
trastuzumab 
Analysis of samples from subjects who received utomilumab and 
trastuzumab is optional.  
ClinicalTrials.gov 
PRIMARY 
OUTCOME 
Incidence of dose-limiting toxicities (DLTs) within the first 
2 cycles (up to about 2 months) reported for Dose-finding 
Cohorts 1 (ado-trastuzumab emtansine) and 2 (trastuzumab).  
Subjects lost to follow-up before completion of first 2 cycles due to 
reasons unrelated to treatment-related adverse events are not 
evaluable for DLT. 


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ClinicalTrials.gov 
SECONDARY 
OUTCOMES 
 Objective tumor response rate (ORR) after 2 cycles for subjects 
in Expansion Phase 1B Cohort 1 (ado-trastuzumab emtansine), 
per RECIST v1.1 (for solid tumors per Appendix 1) 
 Time-to-event measures, for subjects in Expansion Phase 1B 
Cohort 1 (ado-trastuzumab emtansine) who have at least 1 
on-study tumor assessment: 
o Time-to-tumor response (TTR), per RECIST v1.1 
(see Appendix 1), in subjects that respond within 4 months. 
o Duration of response (DR), per RECIST v1.1 
(see Appendix 1), in subjects that respond, through up 
to 5 years after treatment.  
o Progression-free survival (PFS) of subjects (percentage) who 
initiate treatment, reported as the number who remain alive 
without progression 6 months after treatment.  Subjects 
withdrawn for treatment-related AEs, or lost to follow-up 
before 6 months, will report as the last date known alive  
 Incidence of all adverse events (not including laboratory 
abnormalities) while receiving treatment and within 30 days, 
reported by treatment group for severity (as graded by NCI 
CTCAE v5), seriousness (YES/no), and relationship to the study 
treatments  
 Incidence of laboratory abnormalities reported by treatment 
group for severity (as graded by NCI CTCAE v5)  
KEY ELIGIBILITY 
CRITERIA 
Eligibility criteria are extensive.  Eligible subjects are cancer 
patients in otherwise general good health (ECOG 0 to 1), with a 
history of biopsy-proven HER2-overexpressing breast cancer and 
radiographic evidence of metastatic disease, or locally recurrent 
unresectable disease.  Acceptable methods of contraception 
required.  
See Eligibility Criteria and Participant Eligibility Checklist at 
Section 3.1. 


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TREATMENT 
SUMMARY 
Study Rationale 
Utomilumab is a new molecular entity that binds to human 4-1BB 
with high affinity and specificity.  In vitro and in vivo data 
demonstrated significant immunomodulatory activity and 
anti-tumor activity of utomilumab when dosed as a single agent and 
in combination with ADCC-inducing antibodies.  Preclinical and 
the ongoing phase 1 first-in-human studies have shown favorable 
PK properties and safety profiles suggest that it may be 
well-tolerated when administered IV. 
Based upon the above considerations, this phase 1B study will 
assess the safety and identify the recommended phase 2 dose 
(RP2D) of utomilumab in subjects with advanced/metastatic 
HER2-overexpressing breast cancer in combination with 
ado-trastuzumab emtansine or trastuzumab.  During 
dose-escalation, consecutive dose cohorts of subjects will receive 
utomilumab (20 or 100 mg) administered once every 3 weeks as an 
IV infusion in conjunction with ado-trastuzumab emtansine or 
trastuzumab.  During dose-expansion, 2 cohorts (one for each 
combination regimen) will accrue subjects to the selected dose of 
utomilumab. 
Treatment with study drugs will continue until completion of 
24 cycles of treatment (up to about 18 months), confirmed disease 
progression, subject refusal, unacceptable toxicity, whichever 
occurs first, or the study is prematurely terminated by the Sponsor, 
or one of the other reasons for subject withdrawal as specified in 
Section 4.8 will occur.  Treatment beyond 24 cycles (18 months) 
will be allowed only if reviewed and approved by the Principal 
Investigator.  
Based on preclinical studies and the ongoing phase 1 trial, the 
utomilumab dosing will begin at 20 mg, then step to 100 mg.  
Given the scientific rationale and preclinical data suggesting 
synergistic effect of utomilumab given in combination with 
ADCC-inducing mAbs, this study will primarily assess the safety 
and determine the utomilumab RP2D given in combination with 
trastuzumab or ado-trastuzumab emtansine.  In both dose-escalation 
and expansion cohorts, subjects will be assessed for DLTs for the 
first 2 cycles of treatment.  PK and immunogenicity of utomilumab 
and ado-trastuzumab emtansine or trastuzumab will be assessed, 
and pharmacodynamic (PD) markers of immunomodulatory activity 
will be examined. 


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SAMPLE SIZE 
Up to 30 subjects, to achieve 25 evaluable subjects. 
 Up to a maximum of 20 subjects in Cohort 1 (utomilumab plus 
ado-trastuzumab emtansine), consisting of 3 subjects who 
receive utomilumab 20 mg IV, and up to 17 who receive 
utomilumab 100 mg IV.  Subject replacement shall not exceed 5 
additional subjects. 
 5 subjects in Cohort 2 (utomilumab and trastuzumab).   
Cohort 2 closed in January 2020. 
Study Schema 
 
It is to note that other more complex adaptive trial designs were considered, however as just 
2 doses of utomilumab will be tested in combination with ado-trastuzumab emtansine or 
trastuzumab, and as the safety of utomilumab IV has been well tolerated to date in combination 
with other ADCC-inducing mAbs (with defined PK), the following dosing scheme has been 
devised as an efficient means to arrive at the RP2D: 
Due to differences in eligibility between Cohort 1 and Cohort 2, dose-finding and 
dose-escalation are not dependent between cohorts, and may occur at different times.  Accrual to 
both cohorts for dose-finding and dose-escalation will occur in parallel to optimize efficiency in 
dose-finding.  


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Cohort 1 ado-trastuzumab emtansine: 
Dose Level 1 – Utomilumab 20 mg IV + ado-trastuzumab emtansine (T-DM1) 3.6 mg/kg IV 
every 3 weeks.  3 subjects will be treated at this dose level.  If no DLT events are recorded, then 
utomilumab dose will be increased to 100 mg (Dose Level 2, below).  If 1 DLT is observed 
amongst the first 3 subjects, then Dose Level 1 will be expanded to 6 subjects.  If no further 
DLTs are observed, then utomilumab will proceed to 100 mg (Dose Level 2).  If 2 (or more) 
DLTs are recorded at Dose Level 1, enrollment in the ado-trastuzumab emtansine + utomilumab 
cohort will be terminated.  
Dose Level 2 – Utomilumab 100 mg IV + ado-trastuzumab emtansine 3.6 mg/kg IV every 
3 weeks.  3 subjects will be dosed initially.  If one DLT is observed, Dose Level 2 will be 
expanded to 6 subjects.  If no further DLTs are observed, then utomilumab 100mg IV + 
ado-trastuzumab emtansine 3.6 mg/kg IV will be expanded to 9 subjects to gain further 
confidence in the RP2D determination.  If no DLTs are observed in the first 3 subjects, then 
Dose Level 2 will also be expanded to 9 subjects total to define the RP2D.  If more than 2 DLTs 
are recorded in Dose Level 2, then by definition the MTD will be exceeded, and dosing will be 
decreased to utomilumab 20 mg/kg IV (Dose Level 1), with enrollment to the Dose Level 1 
cohort to a total of 9 subjects.  If ≤ 2 DLTs are observed in 9 subjects at Dose Level 1 
(utomilumab = 20 mg/kg IV), then utomilumab 20 mg/kg IV in combination with 
ado-trastuzumab emtansine 3.6 mg/kg IV will be the RP2D. 
Cohort 2 trastuzumab (closed January 2020 with 5 subjects enrolled) 
Dose Level 1 – Utomilumab 20 mg IV + trastuzumab 6 mg/kg IV every 3 weeks.  3 subjects will 
be treated at this dose level.  If no DLT events are recorded, then utomilumab dose will be 
increased to 100 mg (Dose Level 2, below).  If 1 DLT is observed amongst the first 3 subjects, 
then Dose Level 1 will be expanded to 6 subjects.  If no further DLTs are observed, then 
utomilumab will proceed to 100 mg (Dose Level 2).  If 2 (or more) DLTs are recorded at 
Dose Level 1, enrollment in the trastuzumab + utomilumab cohort will be terminated.  
Dose Level 2 – Utomilumab 100 mg IV + trastuzumab 6 mg/kg IV every 3 weeks.  3 subjects 
will be dosed initially.  If one DLT is observed, Dose Level 2 will be expanded to 6 subjects.  If 
no further DLTs are observed, then utomilumab 100 mg IV + trastuzumab 6 mg/kg IV will be 
expanded to 9 subjects to gain further confidence in the RP2D determination.  If no DLTs are 
observed in the first 3 subjects, then Dose Level 2 will also be expanded to 9 subjects total to 
define the RP2D.  If more than 2 DLTs are recorded in Dose Level 2, then by definition the 
MTD will be exceeded, and dosing will be decreased to utomilumab 20 mg/kg IV, with 
enrollment to the Dose Level 1 cohort to a total of 9 subjects.  If ≤ 2 DLTs are observed in 
9 subjects at Dose Level 1 (utomilumab = 20 mg/kg IV), then utomilumab 20 mg/kg IV in 
combination with trastuzumab 6 mg/kg IV will be the RP2D. 
Expansion Phase 1B Cohort 1 (ado-trastuzumab emtansine) – Utomilumab given IV at the 
RP2D in combination with ado-trastuzumab emtansine 3.6 mg/kg IV, will be based on Minimax 
Simon 2 Stage Design.  The null hypothesis that the true response rate is 5% will be tested 
against a one-sided alternative.  In 17 response-evaluable subjects, if there are no responses, the 
study will be terminated.  If 1 or more responses are observed, it will be recommended to 
conduct a future formal phase 2 trial of the combination under a separate study protocol. 


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21 September 2020 
Expansion Phase 1B Cohort 2 (trastuzumab) – Utomilumab given IV at the RP2D in 
combination with trastuzumab 6.0 mg/kg IV, will be based on Minimax Simon 2 Stage Design.  
The null hypothesis that the true response rate is 5% will be tested against a one-sided 
alternative.  In 17 response-evaluable subjects, if there are no responses, the study will be 
terminated.  If 1 or more responses are observed, it will be recommended to conduct a future 
formal phase 2 trial of the combination under a separate study protocol.  
Additional considerations in the design and conduct of this trial: 
Subjects will continue treatment at the assigned dose level and schedule until unacceptable 
toxicity, subject’s voluntary withdrawal, or documentation of progressive disease as determined 
by RECIST v1.1 criteria (see Section 7.2 regarding clinical interpretation of potential “flare” 
tumor responses seen with immunotherapeutic drugs, such as utomilumab).  If 
ado-trastuzumab emtansine (T-DM1) or trastuzumab must be discontinued (eg, for toxicity), the 
patient may remain on single-agent utomilumab until disease progression.  The converse is also 
true (ie, if utomilumab is discontinued, the patient may remain on ado-trastuzumab emtansine or 
trastuzumab until disease progression.  Administration of the study drug utomilumab may 
continue for up to 24 cycles (18 months).  


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1.   
BACKGROUND 
1.1. 
4-1BB Target Biology and Mechanism of Action 
4-1BB (CD137, TNFRSF9), first identified as an inducible costimulatory receptor expressed on 
activated T-cells, is a membrane spanning glycoprotein of the tumor necrosis factor (TNF) 
receptor superfamily.  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 (Wang, et al, 2009), and 
activated B-cell s (Zhang, et al, 2011)(Figure 1).  4-1BB expression has also been demonstrated 
on tumor vasculature (Broll, et al, 2001, Seaman, et al, 2007) and atherosclerotic endothelium 
(Olofsson, et al, 2008).  The ligand that stimulates 4-1BB (4-1BBL) is expressed on activated 
antigen-presenting cells (APCs);  myeloid progenitor cells;  and hematopoietic stem cells.   
 
Figure 1.  Mechanism of CD137, 4-1BB modulation 
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 (Chan, et al, 2007).  Some members of the TNFRSF 
can cleave the extracellular domain from the cell surface and exist in a soluble form.  Soluble 


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4-1BB and soluble 4-1BBL have been demonstrated in the serum of some patients with 
autoimmune diseases and cancers (Michel, et al, 1998;  Furtner, et al, 2005;  
Hentschel, et al, 2006).  Upon 4-1BB activation, TRAF1 and TRAF2, pro-survival members of 
the TNFR-associated factor (TRAF) family are recruited to the 4-1BB cytoplasmic tail resulting 
in downstream activation of NFkB and the Mitogen Activated Protein (MAP) Kinase cascade 
including Erk, Jnk, and p38 MAP kinases.  NFkB activation leads to upregulation of Bfl-1 and 
Bcl-XL, pro-survival members of the Bcl-2 family.  The pro-apoptotic protein Bim is 
downregulated in a TRAF1 and Erk dependent manner (Sabbagh, et al, 2008). 
Numerous studies of murine and human T-cells indicate that 4-1BB promotes enhanced cellular 
proliferation, survival, and cytokine production (Croft 2009).  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 (Lynch 2008).  4-1BB agonists also inhibit autoimmune reactions in a variety 
of autoimmunity models (Vinay, et al, 2006).  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. 
utomilumab, 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.  Injection with utomilumab has been shown to correlate with tumor cell line growth 
inhibition in xenogenic tumor models as a single agent.  In addition, 4-1BB agonist mAbs 
demonstrate significant combinatorial efficacy with ADCC antibodies in lymphoma and breast 
cancer 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. 
1.2. 
Preclinical Profiles of Utomilumab 
1.2.1.  In vitro Data 
Utomilumab has shown immunomodulatory activity in various in vitro assays.  In concert with a 
signal through the T-cell receptor, utomilumab has been shown to mediate ligation of 4-1BB, 
which results in release of soluble 4-1BB (sCD137), activation of NFkB, production of cytokines 
and chemokines (including IL2 and CCL22) and proliferation of antigen-specific CD8+ T-cells 
(Fisher et al., 2012). 
Interaction of 4-1BB on activated normal human B-cell s with its ligand at the time of B-cell  
receptor engagement stimulates proliferation and enhances survival (Zhang, et al, 2011).  The 
potential impact of 4-1BB engagement in B-cell lymphoma has been investigated in 2 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 
(Houot, et al, 2011).  The addition of 4-1BB agonists to in vitro cultures of B lymphoma cells 
with rituximab and NK cells resulted in increased lymphoma killing (Kohrt, et al, 2010).  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. 


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1.2.2.  In vivo Data 
In pre-clinical studies, utomilumab has exhibited the ability to increase lymphocyte proliferation.  
In small animal models developed to test the in vivo function of utomilumab, utomilumab was 
able to enhance expansion of human leukocytes in a dose-dependent manner as evidenced by an 
increase in the proportion of human CD45+ cells in the peripheral blood of engrafted mice.  
Similarly, a dose-dependent increase in the proportion of human leukocytes expressing the 
proliferation marker Ki-67 was noted.  In addition, utomilumab treatment of cynomolgus 
monkeys in single or multiple dose studies increased proliferation among cytotoxic central 
memory T-cells (CD8 TCM) in PBMC samples.  Taken together, these data demonstrate 
evidence of utomilumab’s ability to enhance lymphocyte response in vivo with human PBMC 
from a healthy volunteer donor prior to injection in all cases.  Once tumors were established, 
animals were treated with utomilumab.  Utomilumab was found to be efficacious against all 
3 tumor types.  An example growth curve demonstrating the response to a prostate carcinoma is 
shown in Figure 2.  (Fisher, et al, 2012). 
 
Figure 2.  Effect of PF-05082566 (utomilumab) on the growth of PC3 prostate carcinoma in a huPBL 
SCID model PF-05082566 (utomilumab) inhibits the growth of the PC3 prostate carcinoma in vivo.  
Panel A:   Mean tumor volume at each time point measured.  Panel B: Volume of each tumor on the final 
study day (Day 21).  The mean and SEM are indicated by bars.  *p < 0.05, ** p < 0.005. 
1.2.3.  Clinical Experience 
Utomilumab has been administered to a total of 390 subjects (see Table 1). 
In Study B1641001, 180 subjects with advanced solid tumors and hematological malignancies 
received utomilumab in a dose range between 0.006 and 10.0 mg/kg.  In this study, 114 subjects, 
mainly with advanced solid tumors, received single-agent utomilumab and 66 subjects with 
non-Hodgkin’s lymphoma (NHL) received utomilumab in combination with rituximab.  
In Study B1641003, utomilumab has been administered to 23 subjects with advanced solid 
tumors in a dose range between 0.45 mg/kg and 5.0 mg/kg in combination with pembrolizumab.  
In Study B1641004, utomilumab has been administered to 24 subjects with advanced solid 
tumors, in a dose range between 1.2 mg/kg and 5 mg/kg in combination with mogamulizumab.  


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In Study B9991004, 153 subjects received utomilumab at dose levels of 20 mg, 100 mg, and 
500 mg in combination with avelumab.  
In Study B0601002, utomilumab has been administered to 10 subjects at 20 mg in combination 
with PF-04518600.  
The ongoing first-in-patient clinical Study B1641001 is a phase 1, open–label, dose-escalation 
study.  In study Portion A, utomilumab is administered as a single agent in subjects with 
advanced solid tumors or relapsed or refractory B-cell lymphoma, and in study Portion B, 
utomilumab is given in combination with rituximab in subjects with relapsed or refractory 
CD20+ NHL.  The key study parameters assessed include: safety, tolerability PK/PD markers of 
activity, and preliminary utomilumab anti-tumor activity.  
Study B1641003, a phase 1, open-label, dose-escalation study designed to evaluate the safety, 
and PK/PD of utomilumab administered in combination with pembrolizumab to adults with 
advanced solid tumors, has been completed.  The study also aimed to: assess preliminary 
anti-tumor activity, estimate the MTD and select the RP2D for the combination.  The study was 
halted following completion of the dose-escalation phase.  The dose expansion phase of the 
study was not conducted.  The decision to terminate the study was made for strategic reasons, 
and was not due to any safety or efficacy concerns related to the combination treatment.  A 
completed CSR is available for Study B1641003. 
The ongoing clinical Study B1641004 is a phase 1b, open label, multi-center, multi-dose, 
dose-escalation study designed to evaluate the safety, and PK/PD of utomilumab administered in 
combination with mogamulizumab to adults with defined advanced solid tumors.  The study will 
assess preliminary anti-tumor activity, and will estimate the MTD and RP2D for the 
combination.  
The ongoing clinical Study B9991004 is a phase 1b/2, open label, multi-center, multiple dose, 
study designed to evaluate the safety, clinical activity, PK/PD of avelumab in combination with 
increasing dose levels of other immune modulators in adult subjects with locally advanced or 
metastatic solid tumors.  Combination A of this study includes utomilumab in combination with 
avelumab.  The study aims to determine the RP2D(s) of the combination of utomilumab and 
avelumab in subjects with NSCLC.  The phase 2 component of the study evaluates efficacy and 
further evaluates safety of the combination in subjects with NSCLC, melanoma, head and neck 
cancer, triple negative breast cancer, and small cell lung cancer.  
The ongoing clinical Study B0601002 is a phase 1, open label, multi-center, multiple-dose, 
dose-escalation, safety, and PK/PD study that in Part A evaluates the single agent activity of 
PF-04518600 (OX-40 agonist) and in Part B evaluates the combination of PF-04518600 and 
utomilumab in subjects with select locally-advanced or metastatic carcinomas.  The primary 
objective is to assess safety and tolerability at increasing dose levels of PF-04518600 in 
combination with utomilumab and to estimate the MTD of the combination.  Secondary 
objectives include the overall safety profile, PK/PD, and anti-tumor effects of the combination.  
The clinical data reported in the following sections are based on all available data as of the data 
cut-off of 06 July 2017 for Studies B1641001, B1641003, and B1641004. 


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Table 1. Clinical Studies of Utomilumab (PF-05082566) 
Protocol 
Title 
Subjects 
Planned 
Treated 
Status 
B1641001 
A Phase 1 Study of PF-05082566 as a Single Agent in Patients 
with Advanced Cancer, and in Combination with Rituximab in 
Patients with Non-Hodgkin's Lymphoma (NHL) 
72 to 161 
180 
Ongoing 
B1641003 
A Phase 1 Study of the 4-1BB Agonist PF-05082566 in 
Combination With the PD-1 Inhibitor MK-3475 in Patients with 
Advanced Solid Tumors 
45 to 75 
23 
Completed 
B1641004 
A Phase 1b Study of PF-05082566 in Combination With 
Mogamulizumab (KW-0761) in Patients With Advanced Solid 
Tumors 
70 
24 
Ongoing 
B9991004 
A Phase 1b/2 Open-Label Study to Evaluate Safety, Clinical 
Activity, Pharmacokinetics and Pharmacodynamics of Avelumab 
(MSB0010718C) in Combination with Other Cancer 
Immunotherapies in Patients with Advanced Malignancies 
(Avelumab IB version 7, 31 March 2017) 
317 
153 
Ongoing 
B0601002 
A Phase 1 Open Label, Dose Escalation Study of PF-04518600 as 
a Single Agent and in Combination with PF-05082566 in Patients 
with Selected Locally Advanced or Metastatic Carcinomas 
(PF-04518600 IB December 2016) 
190 
10 
Ongoing 
Safety and Efficacy 
As of the data cut-off date of 06 July 2017, the safety and efficacy of utomilumab are being 
evaluated in 3 studies within the utomilumab clinical program, 2 of which are ongoing 
(B1641001 and B1641004) and 1 is completed (B1641003). Utomilumab is being evaluated both 
as a single agent (B1641001 Portion A) and in combination with other anti-cancer treatments 
(B1641001 Portion B, B1641003, and B1641004). 
For B1641001, safety and efficacy data were recorded for 114 subjects in Portion A (74 [64.9%] 
male and 40 [35.1%] female; mean age of 60.9 years) treated with utomilumab in dose levels 
between 0.006 and 10 mg/kg, and 66 subjects in Portion B (37 [56.0%] male and 
29 [43.9%] female; mean age of 62.1 years) treated with utomilumab in dose levels between 
0.03 and 10 mg/kg in combination with rituximab at 375 mg/m2. 
For B1641003, safety and efficacy data were recorded for 23 subjects (14 [60.9%] males and 
9 [39.1%] females; mean age of 58.0 years) treated with utomilumab in dose levels between 
0.45 and 5.0 mg/kg in combination with 2 mg/kg of pembrolizumab. 
For B1641004, safety and efficacy data were recorded for 24 subjects (19 [79.1%] males and 
5 [20.8%] females; mean age of 63.9 years) treated with utomilumab in dose levels between 
1.2 and 5 mg/kg, in combination with 1 mg/kg of mogamulizumab. 
Since Studies B1641001 and B1641004 are ongoing, the available data are subject to change.  
Study B1641003 is completed and the final clinical study report (CSR) is available.  


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Dose-limiting Toxicities 
There were no dose-limiting toxicities (DLTs) in Study B1641001 either for utomilumab as a 
single agent in Portion A or in combination with rituximab in Portion B. 
There were no DLTs reported in Studies B1641003 nor B1641004.  
A summary of treatment emergent adverse events (TEAEs) occurring or worsening during the 
time from the first dose of study treatment to at least 30 days after the last dose of study 
treatment by System Organ Class (SOC), Medical Dictionary for Regulatory 
Activities (MedDRA), Preferred Term (PT), and maximum CTCAE Grade (all-causality and 
treatment-related) for Portion A is as follows.  The most commonly reported TEAEs (88.6% of 
subjects, all grades), regardless of causality, were in the SOCs of gastrointestinal 
disorders (51.8%);  general disorders and administration site conditions (46.5%);  nervous 
system disorders (28.9%);  musculoskeletal and connective tissue disorders (24.6%);  
metabolism and nutrition disorders (22.8%);  respiratory;  thoracic and mediastinal 
disorders (19.3%);  skin and subcutaneous tissue disorders (17.5%);  infections and 
infestations (15.8%);  investigations (14.0%);  and blood and lymphatic system 
disorders (13.2%).  The most frequently reported TEAEs (≥ 10% of all subjects, all grades) 
regardless of causality were: fatigue (29.8%);  nausea (21.1%);  abdominal pain (14.9%);  
decreased appetite (14.9%);  vomiting (14.0%);  diarrhea (12.3%);  dizziness (12.3%);  
pyrexia (11.4%);  anemia (10.5%);  and constipation (10.5%).  There were four Grade 5 AEs 
reported (disease progression [2 subjects], respiratory failure and malignant neoplasm 
progression [1 subject each]), which were considered to be not related to the study drug. 
The most commonly reported TEAEs (≥ 10% of all subjects; all grades) that were considered 
treatment-related were in the SOCs of general disorders and administration site 
conditions (21.1%);  gastrointestinal disorders (17.5%);  and skin and subcutaneous tissue 
disorders (10.5%).  The most frequently observed treatment-related TEAE (41.2% of subjects; 
all grades) was fatigue (14.0%).  Treatment-related TEAEs were mostly Grade 1 or 2 with only 
four Grade 3/4 AEs reported (colitis;  diarrhea;  fatigue;  hyperbilirubinemia and hyponatremia);  
Grade 3/4 colitis  and diarrhea were observed in the same subject.  No Grade 5 treatment-related 
AEs were observed. 
A summary of TEAEs by SOC, MedDRA PT, and maximum CTCAE Grade (all-causality and 
treatment-related) for Portion B is as follows.  The most commonly reported TEAEs (≥10% of 
subjects; all grades), regardless of causality, were in the SOCs of general disorders and 
administration site conditions (48.5%);  gastrointestinal disorders (45.5%);  musculoskeletal and 
connective tissue disorders (39.4%);  respiratory;  thoracic and mediastinal disorders (36.4%);  
injury;  poisoning and procedural complications and nervous system disorders (30.3% each);  
infections and infestations (27.3%);  skin and subcutaneous tissue disorders (25.8%);  
investigations (24.2%);  blood and lymphatic system disorders (16.7%);  psychiatric 
disorders (12.1%).  The most frequently reported TEAEs (≥10% of subjects; all grades) 
regardless of causality were: fatigue (28.8%);  infusion-related reaction (21.2%);  
cough (16.7%);  pyrexia (13.6%);  upper respiratory tract infection (13.6%);  diarrhea (12.1%);  
headache (10.6%);  and blood creatinine increased (10.6%).  There was one Grade 5 AE (death) 
reported (due to disease progression), which was considered not-related to the study drug.   


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The most commonly reported TEAEs (all grades) that were considered treatment-related were in 
the SOCs of general disorders and administration site conditions (28.8%);  gastrointestinal 
disorders (25.8%);  injury, poisoning and procedural complications (24.2% );  nervous system 
disorders (16.7%);  and skin and subcutaneous tissue disorders (15.2%).  The most commonly 
reported treatment-related TEAEs (75.8% of subjects; all grades) that were considered 
treatment-related were infusion-related reaction (21.2%) and fatigue (19.7%).  Note that all of 
the infusion reactions were associated with rituximab infusion.  Treatment-related TEAEs were 
mostly Grade 1 or Grade 2.  Grade 3/4 AEs were reported in 6 subjects: infusion-related reaction 
and neutropenia (2 subjects each), lymphocyte count decreased and neutrophil count 
decreased (1 subject each).  All Grade 3/4 AEs were related to rituximab treatment only, per 
Investigator assessment.  Two of the Grade 3 AEs were related to PF-05082566 (diarrhea and 
neutropenia).  No Grade 5 treatment-related AEs were observed.   
Twenty-three (23) solid tumor subjects were treated with the combination of PF-05082566 and 
pembrolizumab at the fixed dose of 2 mg/kg.  PF-05082566 was administered at different dose 
levels as follows: 5 subjects received 0.45 mg/kg, 3 subjects each received 0.9 mg/kg;  
1.8 mg/kg;  and 3.6 mg/kg;  and 9 subjects received 5 mg/kg. 
A summary of TEAEs by SOC, MedDRA PT, and maximum CTCAE grade (all-causality and 
treatment-related) for B1641003 is as follows.  The most commonly reported TEAEs, regardless 
of causality, were in the SOCs of gastrointestinal disorders (69.6%);  general disorders and 
administration site conditions (65.2%);  skin and subcutaneous tissue disorders (60.9%);  
respiratory;  thoracic and mediastinal disorders (56.5%);  metabolism and nutrition disorders;  
and musculoskeletal and connective tissue disorders (52.2% each);  infections and 
infestations (43.5%);  nervous system disorders (39.1%);  investigations (34.8%);  blood and 
lymphatic system disorders (26.1%);  injury, poisoning and procedural complications (21.7%);  
endocrine disorders (17.4%);  ear and labyrinth disorders (8.7%);  cardiac disorders;  eye 
disorders;  hepatobiliary;  neoplasms benign;  malignant and unspecified (includes cysts and 
polyps);  product issues;  reproductive system and breast disorders;  and vascular disorders (4.3% 
each).  The most frequently reported TEAEs (100% of subjects; all grades) regardless of 
causality, were fatigue (43.5%);  cough;  nausea (34.8% each);  decreased appetite (30.4%);  
constipation;  pruritus;  rash maculo-papular and vomiting (26.1% each);  anemia;  
pyrexia (21.7% each);  back pain;  dyspepsia;  rash;  and upper respiratory tract infection (17.4% 
each);  alanine aminotransferase increased;  arthralgia;  asthenia;  dry mouth;  dry skin;  dyspnea;  
fall;  hemoptysis;  hypokalemia;  hyponatremia;  muscle spasms;  musculoskeletal chest pain;  
edema peripheral;  pleural effusion;  pneumonia;  sinusitis;  and stomatitis (13.0% each).  There 
was one Grade 5 AE (death) reported, (due to disease progression), which was considered not 
related to the study drug. 
The most frequently observed treatment-related TEAEs (all grades) were in the SOCs of skin and 
subcutaneous tissue disorders (52.2%);  general disorders;  and administration site 
conditions (47.8%);  gastrointestinal disorders (34.8%);  and metabolism and nutrition 
disorders (21.7%).  The most frequently observed treatment-related TEAEs (78.3% of subjects; 
all grades) were fatigue (34.8%);  rash maculo-papular (26.1%);  pruritus (21.7%);  
pyrexia (17.4%);  nausea;  decreased appetite;  dry skin;  dry mouth (13.0% each).  
Treatment-related TEAEs were mostly Grade 1 or Grade 2.  There were only 2 
treatment-related (PF-05082566 and pembrolizumab) Grade 3 AEs reported in 2 subjects: 


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adrenal insufficiency (no evidence of associated hypophysitis reported) and 
hypokalemia (1 subject each).  No Grade 4 or 5 treatment-related AEs were observed. 
Twenty four (24) solid tumor subjects were treated with the combination of PF-05082566 and 
mogamulizumab at 1 mg/kg.  PF-05082566 was administered at 4 dose levels as follows:  
11 subjects received 1.2 mg/kg;  4 subjects received 2.4 mg/kg;  3 subjects received 5 mg/kg;  
and 6 subjects received 100 mg. 
A summary of TEAEs by SOC, MedDRA PT, and maximum CTCAE Grade (all-causality and 
treatment-related) for B1641004 is as follows.  The most frequently observed TEAEs, regardless 
of causality, were in the SOCs of general disorders and administration site conditions (66.7%), 
gastrointestinal disorders (62.5%), skin and subcutaneous tissue disorders (58.3%), respiratory, 
thoracic and mediastinal disorders (54.2%), infections and infestations (45.8), metabolism and 
nutrition disorders (41.7%).  The most frequently observed TEAEs (100% of subjects; all grades) 
regardless of causality, were fatigue (41.7%);  rash (29.2%);  constipation;  nausea;  diarrhea and 
pyrexia (20.8% each); decreased appetite, pruritus, anemia, dyspnea, and headache (16.7% 
each); abnormal dreams, chills, cough, dehydration, infusion related reaction, insomnia, 
lymphocyte count decreased, and rhinorrhea (12.5% each).  There were no Grade 5 AEs reported 
in this study. 
The most frequently observed treatment-related TEAEs (all grades) were in the SOCs of skin and 
subcutaneous tissue disorders (50%), general disorders and administration site 
conditions (41.7%), gastrointestinal disorders (37.5%), metabolism and nutrition 
disorders (25.0%).  The most frequently observed treatment-related TEAEs (83.3% of subjects; 
all grades) were fatigue;  rash (25.0% each);  diarrhea (20.8%);  nausea;  pyrexia;  abnormal 
dreams;  infusion related reaction and pruritus (12.5% each).  Most treatment-related TEAEs 
were Grade 1/2 in severity.  No Grade 5 treatment-related AEs were observed. 
Discontinuations Due to Adverse Events 
In Portion A, there were 15 adverse events reported in 13 subjects that led to permanent 
discontinuation from treatment with utomilumab.  Only 1 subject with metastatic melanoma 
treated at 1.2 mg/kg permanently discontinued treatment with utomilumab for a Grade 2 AE of 
enterocolitis that was considered related to study drug per Investigator assessment.   
There were no AEs leading to permanent treatment discontinuation reported for subjects treated 
in Portion B. 
No subject permanently discontinued from the study treatment due to a treatment-related AE in 
the pembolizumab plus utomilumab trial.  
In the utomilumab and mogamulizumab at 1 mg/kg trial, 1 subject permanently discontinued 
from the study treatment due to treatment-related Grade 3 pneumonitis. 
Serious Adverse Events 
A total of 41 SAEs (all-causality) were reported in the safety database for 34 subjects who 
received utomilumab in Portion A or Portion B. 
One (1) event each of colitis, diarrhea, enterocolitis, hyperbilirubinemia, decreased appetite, 
dehydration and pneumonitis were reported as treatment-related in 5 subjects. 


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In one case, Pfizer (the manufacturer of utomilumab) does not consider a reasonable possibility 
that hyperbilirubinemia may be attributed to the study drug.  The event occurred approximately 
43 days after the first dose of study drug in a subject who had an ongoing abdominal ascites.  
Significant tests, including baseline bilirubin and liver enzyme levels, abdominal imaging results, 
were not available to determine the causality of the event.  Progression of the underlying disease 
may provide the most plausible cause;  of note, recent MRI showed brain metastases. 
A total of 14 SAEs (all-causality) were reported in the safety database for 10 subjects who 
received utomilumab and pembrolizumab.  None of these SAEs were considered related to 
utomilumab per Investigator assessment.  There was 1 SAE (Grade 2 inflammation) that was 
determined by the investigator as related to pembrolizumab treatment.  There was 1 SAE of 
special interest, a Grade 3 hyperbilirubinemia in the utomilumab 5 mg/kg + pembrolizumab 
2 mg/kg treatment group, which was considered not related to treatment. 
The MTD of utomilumab once every 3 weeks (q3wks) in combination with 2 mg/kg of 
pembrolizumab q3wks was determined to be at least 5 mg/kg (the highest dose evaluated).  
Doses up to utomilumab 5 mg/kg q3wks when combined with pembrolizumab 2 mg/kg q3wks 
were safe and well-tolerated in subjects with advanced solid cancer.  The dose expansion phase 
of the study was not initiated by Pfizer for strategic reasons and therefore, there was insufficient 
information to determine the RP2D. 
In the utomilumab plus mogamulizumab at 1 mg/kg trial, a total of 13 SAEs (all-causality) in 
10 subjects were reported in the safety database.  None of these SAEs were considered 
treatment-related. 
Deaths 
A total of 13 deaths were reported in the safety database for subjects in Portion A or in Portion B 
who received treatment with utomilumab.  One (1) subject in Portion B died of disease 
progression after receiving the first dose of rituximab but was not dosed with utomilumab.  None 
of the deaths were attributed to study treatment.  
A total of 5 deaths were reported in the safety database in the pembrolizumab plus utomilumab 
trial.  None of these were considered related to the treatment with utomilumab. 
In the utomilumab plus mogamulizumab trial, a total of 3 deaths were reported in the safety 
database.  None of these deaths were considered related to the treatment with utomilumab.  One 
(1) subject died of sepsis and 2 subjects died due to neoplasm progression.  None of the deaths 
were attributed to study treatment. 
Laboratory Abnormalities 
Note: As many abnormal laboratory values are not necessarily considered as AEs, the numbers 
presented in this section do not precisely match those in the corresponding AE sections above.  
For subjects who received utomilumab in Portion A, Grade 3 hematology laboratory test 
abnormalities reported were: lymphopenia (21 subjects;  18.9%), anemia (3 subjects;  2.7%), 
neutrophils (absolute) (1 subject;  0.9%).  The Grade 4 hematology laboratory test abnormalities 
reported were:  lymphopenia (2 subjects;  1.8%), neutrophils (absolute) (0 subjects;  0.0%), and 
white blood cells (0 subjects;  0.0%).  The Grade 3 abnormal serum chemistry abnormalities 
reported were: hyponatremia (7 subjects;  6.3%), hypophosphatemia (4 subjects;  3.8%), 
hyperglycemia (3 subjects;  2.7%), alkaline phosphatase increased, hypokalemia, and 


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hypoalbuminemia (2 subjects each;  1.8%), and hypomagnesemia (1 subject each;  0.9%).  The 
only Grade 4 abnormal serum chemistry values were: hypercalcemia (1 subject;  0.8%) and 
hypokalemia (1 subject;  0.9%). 
In Portion B, Grade 3 hematology laboratory test abnormalities reported were: lymphopenia 
(22 subjects;  34.9%), neutrophil count decreased (4 subject each;  6.3%), white blood cell count 
decreased (3 subjects;  4.7%), platelet count decreased (1 subject;  1.5%).  The Grade 4 
hematology laboratory test abnormalities reported were: lymphopenia (4 subjects;  6.3%), and 
neutrophil count decreased (3 subjects;  4.7%). 
The Grade 3 abnormal serum chemistry values reported were: hyperglycemia and 
hypophosphatemia (2 subjects each;  4.4%);  ALT increased, hyperkalemia, hypomagnesemia, 
hypoglycemia, and hyponatremia (1 subject each;  1.5%). 
Laboratory test abnormalities for subjects who received utomilumab and pembrolizumab are 
summarized by maximum CTCAE Grade, as follows.  The Grade 3 hematology laboratory test 
abnormalities reported were: lymphopenia (6 subjects;  26.1%) and anemia (3 subjects;  13.0%).  
The only Grade 4 hematology laboratory test abnormalities reported was lymphopenia (1 subject;  
4.3%).  This was not reported as an AE by the Investigator.  The Grade 3 abnormal serum 
chemistry abnormalities reported were: hypoalbuminemia and hyponatremia (3 subjects each;  
13.0%), hyperglycemia, hypokalemia, and hypophosphatemia (2 subjects each;  8.7%), alkaline 
phosphatase increased and bilirubin increased (1 subject each;  4.3%).  Both alkaline 
phosphatase increased and bilirubin increased were considered related to metastatic disease.  The 
only Grade 4 abnormal serum chemistry values reported was hyponatremia (1 subject;  4.3%).  
This hyponatremia occurred in the subject with adrenal insufficiency. 
Laboratory test results for subjects who received utomilumab and mogamulizumab in B1641004 
is summarized by maximum CTCAE Grade.  The Grade 3 hematology laboratory test 
abnormalities reported were: lymphopenia (7 subjects;  29.2%) and anemia (2 subjects;  8.3%);  
and in Grade 4 only lymphopenia (1 subject;  4.1%) was reported.  The Grade 3 serum chemistry 
abnormalities reported were: hyperglycemia (3 subjects;  12.5%), hypophosphatemia (2 subjects;  
8.3%), and hyponatremia (1 subject;  4.1%).  There were no Grade 4 hematology or Grade 3/4 
serum chemistry abnormalities reported. 
ECG and Vital Signs 
In both Portion A and B, as well as the pembrolizumab plus utomilumab combination, and in the 
utomilumab plus mogamulizumab combination, there were no observed QTc prolongations 
(≥ 500 msec) or changes from baseline QTcF (≥ 60 msec) that were considered clinically 
significant per Investigator assessment.  
In both Portion A and B, as well as the utomilumab plus pembrolizumab combination, there were 
no observed heart rates (< 50 bpm and > 120 bpm) or change in heart rate (decrease/increase 
from baseline ≥ 30 bpm) that were considered clinically significant, per Investigator assessment.  
In both Portion A and B, there were no observed blood pressure measurements 
(decrease/increase baseline systolic ≥ 30 m Hg or baseline diastolic blood pressure ≥ 20 mm Hg) 
that were considered clinically significant per Investigator assessment. 


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Safety Summary 
In summary, the observed safety profile, based on a data cut-off date of 06 July 2017 for 
B1641001, support the use of utomilumab both as a single agent and in combination with 
rituximab.  Treatment-related AEs were generally mild or moderate with four Grade 3/4 AEs 
(colitis;  diarrhea;  hyponatremia;  hyperbilirubinemia;  and fatigue) reported as related to 
PF-5082566 in Portion A.  The observed safety profile supports utomilumab use in combination 
with pembrolizumab.  Treatment-related AEs were generally mild or moderate, with only two 
Grade 3 AEs reported as treatment-related to both utomilumab and pembrolizumab.  In addition, 
the observed safety profile, based on a data cut-off date of 06 July 2017 for B1641004, supports 
utomilumab in combination with mogamulizumab.  Treatment-related AEs were generally mild 
or moderate and Grade 1 or Grade 2 in severity. 
Pharmacokinetics and Product Metabolism in Humans 
Study B1641001:  A Phase I Study of PF-05082566 As A Single Agent In Subjects With 
Advanced Cancer, And In Combination With Rituximab In Patients With Non-Hodgkin’s 
Lymphoma (NHL). 
The phase 1 first in human (FIH) study of utomilumab is currently ongoing.  This is an 
open-label, multi-center, multiple-dose study of single agent utomilumab in subjects with solid 
tumors or relapsed or refractory B-cell lymphoma (Portion A) and of utomilumab in combination 
with rituximab in subjects with relapsed or refractory CD20 positive NHL (Portion B). 
Preliminary median utomilumab concentration versus time profiles for subjects in Portion A 
(utomilumab alone) and Portion B (utomilumab + rituximab) after single dose (Cycle 1) are 
depicted in Figure 3.  The utomilumab exposure after single dose appeared to increase with 
increasing doses.  The utomilumab terminal half-life (t1/2) ranged from 208 to 349 hours in 
Portion A and from 274 to 550 hours in Portion B, respectively.  The utomilumab AUCinf was 
slightly higher in Portion B than that in Portion A at corresponding dose levels. 


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Figure 3.  Left Panel:  Portion A (utomilumab alone);  Right Panel:  Portion B (utomilumab + rituximab).  
Utomilumab exposure appeared to increase with increasing doses. 
Population Pharmacokinetic Modeling 
Preliminary population PK analysis has been conducted using data from 68 subjects (n = 41 in 
Portion A and n = 27 from Portion B) receiving doses from 0.006 to 5 mg/kg Q4W using serial 
and sparse PK samples in Study B1641001.  A two-compartment model with linear elimination 
best described these data.  Among the covariates tested, both baseline body weight and treatment 
portion had statistically significant effect on clearance (CL).  Baseline body surface area and 
gender were found to significantly correlate with central volume of distribution (Vc).  No other 
covariates had a statistically significant effect on either CL or Vc.  Simulations were performed 
at various dosing schedules which indicated that the exposure at dose levels higher than 
0.12 mg/kg was above the assumed efficacious concentration (Ceff, 1730 ng/mL) with both once 
every 3 weeks (Q3W) and once Q4W schedule.  Although body weight was identified as a 
significant covariate on CL, it accounted for only a small percentage (~< 7%) of the 
inter-individual variability in serum utomilumab exposure.  In addition, simulations indicated 
that utomilumab exposure is similar between body weight based and fixed dosing regimens.  
Therefore, this suggests the possibility of using a fixed dosing regimen in future utomilumab 
clinical studies.   
Immunogenicity 
Anti-drug antibodies (ADA) to utomilumab in human serum were determined by a validated, 
quasi-quantitative bridging electro chemi-luminescence method.  Preliminary analyses based on 
quality-controlled, non-quality-assured data are presented.  
In Portion A, 9 of 61 subjects (14.8%) exhibited positive ADA prior to treatment with 
utomilumab.  35 of 61 subjects (57.4%) were positive for ADA for at least 1 time point 


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regardless of baseline ADA status.  Among 35 ADA-positive subjects, 7 (20%) exhibited 
positive neutralizing antibody (Nab) against utomilumab.  
In Portion B, 2 of 41 subjects (4.9%) exhibited positive ADA against utomilumab prior to 
treatment with utomilumab plus rituximab.  3 of 41 subjects (7.3%) were positive for ADA for 
at least 1 time point regardless regardless of baseline ADA status when administered in 
combination with rituximab.  Among 3 ADA-positive subjects, 1 (33.3%) exhibited positive Nab 
against utomilumab.  
The impact of ADA on PK of utomilumab was characterized.  ADA-negative subjects were 
defined as those with negative antibody status for all samples collected during the study 
including baseline (pre-treatment).  ADA-positive subjects were defined as those with at least 
1 positive ADA sample anytime during the study including baseline (pre-treatment).  
Utomilumab clearance (CL) was similar in ADA-negative and ADA-positive subjects suggesting 
that ADA status had minimal impact on the PK of utomilumab (see Figure 4). 
 
Figure 4.  Effect of ADA on utomilumab Clearance (Study B1641001 Portion A). 


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In study B1641003, 2 out of 23 (8.7%) subjects exhibited positive ADA against utomilumab 
prior to treatment with utomilumab plus pembrolizumab.  The presence of positive ADA at 
baseline was likely due to pre-existing host antibodies that were cross-reactive with utomilumab.  
Seventeen out of 23 subjects (73.9%) were positive for ADA for at least 1 time point regardless 
of baseline ADA status when administered in combination with pembrolizumab.  The overall 
incidence of treatment-induced ADA was 65.2% (15/23 subjects);  7 out of 23 (30.4%) subjects 
exhibited positive Nab against utomilumab.  Similar utomilumab exposure (eg, AUCtau (dn) and 
Cmax (dn)) was observed in subjects with treatment-induced ADA and ADA-negative subjects.  
While mean Cmax (dn) appeared to be lower in subjects with positive NAb, AUCτ (dn) was 
similar in subjects with positive and negative NAb.  
There were 2 (13.3%) out of 15 ADA-positive subjects and 1 (12.5%) out of 
8 ADA-negative subjects who experienced treatment-emergent, all causalities 
hypersensitivity/infusion reactions.  There was 1 (14.3%) out of 7 NAb-positive subjects and 
there were 2 (12.5%) out of 16 NAb-negative subjects who experienced treatment-emergent, all 
causalities hypersensitivity/infusion reactions.  
In addition, the presence of ADA against utomilumab did not preclude subjects from responding 
to the combination treatment.  The response rate was 25% (2 responders out of 8 
ADA-negative subjects) and 26.7 % (4 responders out of 15 ADA-positive subjects) for 
ADA-negative and ADA-positive subjects, respectively.  The response rate was 25% (4 
responders out of 16 NAb-negative subjects) and 28.6% (2 responders out of 7 
NAb-positive subjects) for NAb-negative and NAb-positive subjects, respectively.  Overall, 
there was no detectable impact of ADA/NAb on PK, safety and efficacy.  
In study B1641004, among 10 subjects tested for ADA analysis, none of them exhibited positive 
ADA against utomilumab prior to treatment with utomilumab plus mogamulizumab.  Five out of 
10 subjects (50%) were positive for ADA against utomilumab for at least 1 time point when 
administered in combination with mogamulizumab.  
Efficacy 
Study B1641001:  The anti-tumor activity of single-agent utomilumab in subjects with advanced 
malignancies and utomilumab in combination with rituximab in subjects with CD20-positive 
NHL is being assessed in the Study B1641001.  In this study, tumor responses are reported by 
Investigators per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for Portion 
A subjects and irRECIST for subjects enrolled in the expansion cohort of Portion A or 
International Working Group (IWG) criteria for Portion B.  
For Portion A, BOR observed was 1 CR (0.24 mg/kg; MCC) and 2 PR in MCC subjects (1 at 
0.24 mg/kg, and 1 at 0.60 mg/kg).  One of the PR observed in MCC subject had prior 
IO-experience (0.24 mg/kg).  In the 59 melanoma subjects there were no CR but 1 
PR (0.24 mg/kg) was observed.  There were no confirmed PR and CR in NSCLC subjects.  The 
irRECIST exploratory analysis was consistent with analysis using RECIST 1.1.  
For Portion B, in NHL subjects 4 CR (1 at 0.03 mg/kg, 1 at 0.12 mg/kg, and 2 at 1.20 mg/kg) 
and 9 PR (2 at 0.18 mg/kg, 3 at 1.20 mg/kg, 1 and 1 at 5.0 mg/kg) were observed.  In follicular 
lymphoma subjects, 4CR (1 at 0.03 mg/kg, 1 at 0.12 mg/kg, and 2 treated at 1.20 mg/kg) and 6 
PR (2 at 0.18 mg/kg, 5 at 1.20 mg/kg, 1 at 2.40 mg/kg and 1 at 5.0 mg/kg) was observed.  


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Study B1641003:  The anti-tumor activity of utomilumab in combination with pembrolizumab 
in subjects with advanced solid tumors was assessed in B1641003.  In this study, tumor 
responses are reported by Investigators per RECIST 1.1 (Eisenhauer, et al, 2009).  The tumor 
responses reported below were confirmed by the Investigator on at least 2 consecutive scan 
evaluations.  
Among the 23 subjects treated, 6 had confirmed objective response providing an objective 
response rate (ORR) of 26.1%.  Two (2) subjects had a confirmed CR (1 subject with RCC 
treated at 1.8 mg/kg and 1 subject with SCLC treated at 5.0 mg/kg).  Four (4) subjects achieved a 
PR:  1 subject with RCC and 1 subject with NSCLC treated at 0.45 mg/kg; 1 subject with 
anaplastic thyroid disease treated at 3.6 mg/kg, and 1 subject with SCCHN treated at 5 mg/kg.  
Study B1641004:  Efficacy assessments are ongoing for Study B1641004.  Out of 24 subjects 
evaluated during the utomilumab dose-escalation phase of the study, no RECIST-defined 
complete responses were observed.  One (1) subject had BOR of PR and 9 subjects achieved a 
BOR of SD. 
1.3. 
Trastuzumab and Ado-Trastuzumab Emtansine 
Trastuzumab is a recombinant DNA-derived humanized monoclonal antibody that selectively 
binds with high affinity in a cell-based assay (Kd = 5 nM) to the extracellular domain of the 
human epidermal growth factor receptor 2 protein, HER2.  The antibody is an IgG1 kappa that 
contains human framework regions with the complementarity-determining regions of a murine 
antibody (4D5) that binds to HER2.  The HER2 (or c-erbB2) proto-oncogene encodes a 
transmembrane receptor protein of 185 kDa, which is structurally related to the epidermal growth 
factor receptor (EGFR, aka  HER1).  HER2 protein overexpression is observed in 25% to 30% of 
primary breast cancers.  HER2 protein overexpression can be determined using an 
immunohistochemistry-based assessment of fixed tumor blocks, and HER2 gene amplification 
status can be measured by fluorescence in situ hybridation (FISH) in archival formalin-fixed, 
paraffin-embedded breast tumor tissue specimens.  Trastuzumab has been shown, in both in vitro 
assays and in animals, to inhibit the proliferation of human tumor cells that overexpress HER2.  
Trastuzumab is a mediator of antibody-dependent cellular cytotoxicity (ADCC).  In vitro, 
trastuzumab-mediated ADCC has been shown to be preferentially exerted on HER2 
overexpressing cancer cells compared with cancer cells that do not overexpress HER2. 
In HER2+ metastatic breast cancer trastuzumab is indicated: 1)  in combination with paclitaxel 
for first-line treatment of HER2-overexpressing metastatic breast cancer, or 2)  as a single-agent 
for treatment of HER2-overexpressing breast cancer in patients who have received one or more 
chemotherapy regimens for metastatic disease. 
Ado-trastuzumab emtansine is a HER2-targeted antibody-drug conjugate.  The antibody is the 
humanized anti-HER2 IgG1, trastuzumab.  The small molecule cytotoxin, DM1, is a microtubule 
inhibitor that is covalently linked to trastuzumab via the stable thioether linker MCC 
(4-[N-maleimidomethyl] cyclohexane-1-carboxylate).  Upon binding to sub-domain IV of the 
HER2 receptor, ado-trastuzumab emtansine undergoes receptor-mediated internalization and 
subsequent lysosomal degradation, resulting in intracellular release of DM1-containing cytotoxic 
catabolites.  Binding of DM1 to tubulin disrupts microtubule networks in the cell, which results 
in cell cycle arrest and apoptotic cell death.  In addition, in vitro studies have shown that similar 
to trastuzumab, ado-trastuzumab emtansine inhibits HER2 receptor signaling, mediates 


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antibody-dependent cell-mediated cytotoxicity and inhibits shedding of the HER2 extracellular 
domain in human breast cancer cells that overexpress HER2. 
Ado-trastuzumab emtansine as a single agent, is indicated for the treatment of patients with 
HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, 
separately or in combination.  Patients should have either received prior therapy for metastatic 
disease, or developed disease recurrence during or within six months of completing adjuvant 
therapy.  
1.4. 
Study Rationale 
1.4.1.  Rationale for the Combination of Utomilumab with Ado-Trastuzumab and 
Trastuzumab 
Preclinical Combination Studies 
Antibody dependent cellular cytotoxicity (ADCC) has been hypothesized as a mechanism of 
tumor destruction resulting in direct antigen presentation and in the induction of tumor antigen 
specific T-cell responses (‘cross-priming”).  This is supported by preclinical experiments 
demonstrating that the therapeutic efficacy of an anti-HER2/neu antibody depends on both innate 
and adaptive immunity (Park, et al, 2010). 
The combinatorial anti-tumor activity of ADCC inducing mAb with 4-1BB agonist mAbs was 
assessed in both lymphoma and HER2+ breast cancer models.  A mouse anti-mouse CD20 
antibody with ADCC inducing activity was selected as a surrogate mAb for rituximab.  
MAB9371 was selected as a surrogate for utomilumab, as utomilumab does not cross react with 
murine 4-1BB.  MAB9371 is a commercially available rat anti mouse 4-1BB agonist mAb (R & 
D Systems, Minneapolis MN).  The binding affinity of MAB9371 for murine 4-1BB is similar to 
the affinity of utomilumab for human 4-1BB.  In both models, treatment with a combination of 
surrogate mAbs at concentrations with limited single agent efficacy, showed significant tumor 
growth inhibition (A20 model) and/or enhanced survival (Em-myc model) (Figure 5). 
 
Figure 5.  Combinatorial Efficacy of 4-1BB and CD20 Surrogate mAbs in Lymphoma Models 4-1BB agonist 
antibodies demonstrate significant combinatorial efficacy with ADCC antibodies in transplantable and 


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spontaneous lymphoma models.  A) A20 murine lymphoma cells were implanted on the flank of Balb/C mice.  
Group mean tumor volume measurements at the indicated times are shown above.  Error bars represent SEM.  
Untreated vs single agent p = not significant, untreated vs combination p < 0.01.  B) Survival days post 
treatment.  Median survival was calculated using Graph Pad Prism CD20 = 15 days, 1mpk 4-1BB  = 23.5 days, 
CD20+0.1mpk 4-1BB = 25.5 days, CD20+1mpk 4-1BB = 34 days.  Statistical significance of the 4-1BB 
treatment or combination treatment versus CD20 group was determined using a Log Rank (Mantel-Cox) test 
using Graph Pad Prism software, CD20 vs 4-1BB p < 0.02, CD20 vs CD20 + 0.1mpk 4-1BB p = not 
significant, CD20 vs CD20 + 1mpk 4-1BB p < 0.001. 
Anti-4-1BB agonistic mAb enhances anti-breast cancer activity of trastuzumab in vivo 
(Kohrt, et al, 2012).  The in vivo ability of anti-4-1BB mAbs to enhance trastuzumab’s activity 
was tested in a xenotransplanted human breast cancer (BT474M1 cell line) model in athymic 
mice.  These mice have fully competent NK cells while lacking functional T-cells.  
Anti-4-BB mAb alone had no effect on tumor growth, while trastuzumab had a modest effect 
(Figures 6A and 6C).  Simultaneously, Kohrt explored the effect of trastuzumab and 
anti-4-1BB mAb in various schedules.  Since maximal upregulation of CD137 required 24 hours 
of NK cell exposure to trastuzumab-coated cells in vitro, investigators aimed to determine the 
importance of injection sequence.  Trastuzumab was injected on Day 3 (post-tumor inoculation) 
and anti-4-1BB mAb was injected either on Day 2, 3 or 4.  Treatment was repeated in all groups 
14 days following the first injection.  Of the three combination sequences tested, trastuzumab 
followed by anti-4-1BB mAb resulted in the greatest reduction in tumor size and mortality with 
the opposite order, anti-4-1BB mAb followed by trastuzumab having the least effect both in 
tumor growth (Figure 6A) and survival (Figure 6B). 
Since trastuzumab followed by anti-4-1BB antibodies demonstrated more potent antitumor 
activity in vivo, this injection schedule was chosen for subsequent experiments.  When the 
treatment regimen was repeated weekly for 3 weeks the combination treatment resulted in 
prolonged control of tumor growth and a significant improvement in survival (Figures 6C and 
6D). 
Enhancement of the therapeutic activity of trastuzumab by anti-4-1BB mAb is specific to 
HER2-expressing tumors.  To determine if the synergy between anti-HER2 and 
anti-4-1BB mAbs requires specific recognition by the anti-tumor antibody, two tumors differing 
in HER2 expression were inoculated subcutaneously in individual mice.  On the left flank, mice 
were inoculated with MCF7 cells, which are HER2 low to negative.  On the right flank, mice 
were inoculated with HER18 cells, a transduced derivative of MCF7 cells that stably overexpress 
HER2 (Figure 7A)(12).  Mice then received either trastuzumab monotherapy on Day 3 or the 
combination of trastuzumab on Day 3 and anti-4-1BB mAb on Day 4.  This sequential therapy 
was repeated weekly for 3 successive weeks.  As expected, only the HER2-overexpressing 
tumors responded to monotherapy with trastuzumab.  The addition of anti-4-1BB mAb resulted 
in an enhanced therapeutic effect but only against the HER2-positive tumor that could be 
targeted by the anti-HER2 mAb (Figures 7B-C). 
Anti-4-1BB mAb enhances the therapeutic activity of trastuzumab against a human 
HER2-overexpressing primary breast tumor.  Since the combination of trastuzumab and 
anti-4-1BB antibodies demonstrated increased efficacy against HER2-overexpressing cell lines, 
we next aimed to assess efficacy of the combination therapy using a primary patient  


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Figure 6.  Anti-4-1BB agonistic mAb enhances anti-breast cancer activity of trastuzumab in vivo.  Nu/nu mice were 
inoculated with 5 × 106 BT474M1 breast tumor cells, subcutaneously, on the abdomen 1 day after subcutaneous 
injection of 0.72mg/60 day release beta-estradiol pellet (A-D).  (A-B) Post-tumor inoculation, mice then received 
two cycles of treatment separated by 14 days with either Rat IgG control on Days 3 and 17(●), trastuzumab antibody 
on Days 3 and 17(■), trastuzumab antibody on Days 3 and 17 and anti-4-1BB antibody on Days 2 and 16 (♦), 
trastuzumab antibody on Days 3 and 17 and anti-4-1BB antibody on days 3 and 17 (▼), or trastuzumab antibody on 
Days 3 and 17 and anti-4-1BB antibody on Days 4 and 18 (▲).  Mice (10 per group) were then monitored for tumor 
growth (A, *p < .001) and overall survival (B, *p = .001).  (C-D) To determine if increased frequency of treatment 
using the superior combination regimen mice received 3 weekly treatment with either Rat IgG control starting on 
Day 3(●), trastuzumab antibody starting on Day 3(■), anti-4-1BB antibody starting on day 4(♦), or trastuzumab 
antibody starting on Day 3 and anti-4-1BB antibody starting on Day 4 (▲) with treatment repeated weekly for a 
total of 3 weeks.  Mice (10 per group) were then monitored for tumor growth (C, *p < .001) and overall survival 
(D, *p = .003). 


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xenotransplant model.  A primary HER2-overexpressing-breast tumor was successfully engrafted 
into sub-lethally irradiated SCID mice.  After tumors were established the mice were randomized 
into treatment groups that received either:  rat IgG control, trastuzumab, anti-4-1BB mAb, or 
trastuzumab followed 24 hours later by anti-4-1BB mAb and repeated weekly for a total of 
3 weeks.  The combination of trastuzumab and anti-4-1BB mAb was superior to trastuzumab 
alone, significantly reducing tumor growth and prolonging survival (Figures 7D-E). 
The enhanced efficacy of trastuzumab in combination with anti-4-1BB has been recently 
confirmed with ado-trastuzumab emtansine, which has been previously shown to retain ADCC 
capacity as a mechanism of action in vitro and in vivo (Junttila, et al, 2011;  Barok, et al, 2011;  
English, et al, 2014).  Two murine models have been performed which confirm the synergy 
observed with anti-4-1BB and ado-trastuzumab emtansine combination therapy including a 
HER18 xenograft model and an SU-258 primary breast model (data not shown).  
Overexpression of HER2 is observed in approximately 20% of human breast cancers and is 
implicated in the aggressive growth and poor clinical outcomes associated with these tumors.  
While the development of trastuzumab, pertuzumab, lapatinib and ado-trastuzumab emtansine 
provided patients with HER2-positive tumors a markedly better outcome than with 
chemotherapies, virtually all patients with HER2-positive MBC will eventually progress despite 
these available therapies, leading to mortality.  Opportunities remain to improve outcomes for 
patients with MBC.  Ado-trastuzumab emtansine and trastuzumab have individually 
demonstrated activity in patients with HER2-positive MBC, and additionally, nonclinical data 
showing synergy with the combination of ado-trastuzumab emtansine and anti-4-1BB mAb, and 
between trastuzumab and anti-4-1BB mAb, suggest that investigation of ado-trastuzumab 
emtansine or trastuzumab in combination with anti-4-1BB mAb in patients with HER2-positive, 
locally advanced (unresectable) or metastatic breast cancer is warranted.  Such patients represent 
the patient population eligible for study enrollment. 
1.4.2.  Rationale for Utomilumab and Ado-Trastuzumab/Trastuzumab Doses 
1.4.2.1.  Utomilumab  
Preliminary population PK analysis showed that body weight accounts for only a small 
percentage (~7%) of the variability in drug exposure.  Simulations indicated that utomilumab 
exposure profiles are similar in both body weight and flat utomilumab dosing regimens.  
Therefore, it is suggested a fixed dosing regimen be utilized for ease of use and to minimize 
potential medication errors. 
Active doses for utomilumab ranged from 0.24 mg/kg to 0.6 mg/kg (approximately 20 to 50 mg) 
in Merkel cell carcinoma (MCC) as a single agent.  It is not clear if higher doses might be active 
as limited number of MCC patients were treated at higher doses.  Responses were also observed 
with the combination of utomilumab and rituximab (R) in R-refractory NHL as low as 
0.03 mg/kg with highest active dose of 2.4 mg/kg.  These data suggest that the active dose range 
of utomilumab is quite broad, spanning an approximate 100-fold dose range. 
Flat utomilumab doses of 20 (approximately 0.24 mg/kg), 100 (approximately 1.2 mg/kg), and 
500 mg (approximately 6 mg/kg) are being tested in Pfizer Study B9991004.  In this study, two 
dose levels of utomilumab (20 mg IV, and 100mg IV) will be tested in combination with 
ado-trastuzumab or trastuzumab. 


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Figure 7.  Anti-4-1BB agonistic mAb enhances anti-breast cancer activity of trastuzumab in vivo while retaining HER2 specificity 
against HER2-overexpressing breast cancer cell lines and a primary breast tumor.  Nu/nu mice were inoculated with 5 × 106 MCF7 
breast tumor cells subcutaneously on the left flank and 5 × 106 HER18 breast tumor cells subcutaneously on the right flank 
(A, Schema).  (A-C) Post-tumor inoculation, mice received either trastuzumab on Day 3, or trastuzumab on Day 3 and anti-4-1BB 
antibody on Day 4 with each treatment repeated weekly for a total of 3 weeks.  (B) Mice (10 per group) were monitored for tumor 
growth of MCF7 on the left flank (○) and HER18 on the right flank (☐) in mice treated with trastuzumab, and MCF7 on the left 
flank (●) and HER18 on the right flank (■) in mice treated with trastuzumab and anti-4-1BB mAbs (*p < .001).  
(C) Representative mice (3 of 10 per group) at 25 and 50 days post-tumor inoculation.  SCID mice were inoculated with 1 × 106 
HER2+ primary breast tumor cells (SU-258) by intramammary injection 24 hours after 200 cGy total body irradiation (TBI) (D-E).  
On Day 40 mice were randomized to 1 of 4 groups (5 mice per group) including IgG control with treatment on Day 40 (●), 
trastuzumab on Day 40 (■), anti-4-1BB mAb on Day 41 (♦), or trastuzumab on Day 40 and anti-4-1BB mAb on Day 41 (▲).  
Treatment was repeated weekly in each group for a total of 3 treatments.  Mice were monitored for tumor growth (D, *p = .016) 
and overall survival (E, *p = .002). 


 
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Figure 8.  TDM-1 retains potency against and demonstrates synergistic activity with anti-4-1BB mAb 
therapy against HER2-overexpressing breast cancer, including a HER18 xenograft model (shown), and 
an SU-258 primary breast model (data not shown).  In the HER18 model, Nu/nu mice were inoculated 
with 1 × 106 HER2+ HER18 tumor cells by subcutaneous injection.  On Day 3, mice were randomized.  
In the SU-258 primary model, SCID mice were inoculated with 1 × 106 HER2+ primary breast tumor 
cells (SU-258) by intramammary injection 24 hours after 200 cGy total body irradiation (TBI). 
1.4.2.2.  Ado-Trastuzumab/Trastuzumab 
The dose selection for ado-trastuzumab emtansine (3.6 mg/kg IV q 3 weeks) in this protocol is 
the full FDA-approved dose for patients with HER2+ metastatic breast cancer, and the dose 
selection of trastuzumab (6 mg/kg IV q3 weeks) is the full FDA-approved drug dose for 
treatment of HER2+ metastatic breast cancer. 
2.   
STUDY OBJECTIVES;  ENDPOINTS;  AND OUTCOMES 
2.1. 
Objectives 
Primary Objective: 
 Estimate the maximum tolerated dose (MTD) and determine the recommended dose 
(RP2D) of utomilumab in combination with ado-trastuzumab emtansine (T-DM1) in 
subjects with HER2-positive advanced breast cancer. 
Secondary Objectives: 
 Determine the objective tumor response rate (ORR)  
 Determine the time-to-tumor response (TTR) 


 
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 Determine the duration of response (DR) 
 Determine progression-free survival (PFS)  
 Assess the safety and tolerability of utomilumab in combination with ado-trastuzumab 
emtansine or trastuzumab  
Exploratory Objectives: 
 Evaluate the pharmacokinetics (PK) of utomilumab and ado-trastuzumab emtansine or 
trastuzumab when given in combination  
 Evaluate preliminary evidence of antitumor activity of utomilumab in combination with 
ado-trastuzumab emtansine or trastuzumab  
 Evaluate the immunogenicity of utomilumab and ado-trastuzumab emtansine or 
trastuzumab when given in combination  
 Assess the presence of CD8+ T-cells in HER2-positive tumors  
 Evaluate the modulation of immune activity biomarkers by utomilumab in combination 
with ado-trastuzumab emtansine or trastuzumab. 
Analysis of samples from subjects who received utomilumab and trastuzumab is optional.  
2.2. 
Endpoints 
Primary Endpoint 
 First 2 cycles dose-limiting toxicities (DLTs) 
Secondary Endpoints 
 Objective tumor response rate (ORR) per RECIST v1.1  
 Time-to-event measures: 
o Time-to-tumor response (TTR) 
o Duration of response (DR)  
o Progression-free survival (PFS)  
 Adverse events (not including laboratory abnormalities) as characterized by types, severity 
(as graded by NCI CTCAE v5), timing, seriousness, and relationship to study treatments  
 Laboratory abnormalities as characterized by type, severity (as graded by 
NCI CTCAE v5) and timing  
Exploratory Endpoints: 
 Ctrough and Cmax of utomilumab, ado-trastuzumab emtansine, or trastuzumab  
 Anti-drug antibody level and incidence  
 Tumor tissue biomarkers (including number and percentage of CD8+ T-cells)  
 Peripheral blood and additional tumor tissue biomarkers consisting of the levels of cells, 
DNA, RNA or proteins, such as CD8 T-cells, PD-L1, TCR sequence changes, and 


 
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biomarkers of the IFNpathway, that may be related to anti-tumor immune response 
and/or response to or disease progression on utomilumab in combination with trastuzumab 
or ado-trastuzumab emtansine. 
Analysis of samples from subjects who received utomilumab and trastuzumab is optional.  
2.3. 
ClinicalTrials.gov Outcomes 
Primary Outcome  
Incidence of dose-limiting toxicities (DLTs) within the first 2 cycles (up to 2 months) reported 
for the Dose-finding Cohorts 1 (ado-trastuzumab emtansine) and 2 (trastuzumab).  Subjects 
lost to follow-up before completion of first 2 cycles due to reasons unrelated to 
treatment-related adverse events are not evaluable for DLT.  
Secondary Outcomes 
1. Objective tumor response rate (ORR) after 2 cycles for subjects in Expansion Phase 1B 
Cohort 1 (ado-trastuzumab emtansine), per RECIST v1.1 (see Appendix 1) 
2. Time-to-event measures, for subjects in Expansion Phase 1B 
Cohort 1 (ado-trastuzumab emtansine) who have at least 1 on-study tumor assessment: 
o Time-to-tumor response (TTR), per RECIST v1.1 (see Appendix 1), in subjects 
that respond within 4 months 
o Duration of response (DR), per RECIST v1.1 (see Appendix 1), in subjects that 
respond, through up to 5 years after treatment 
o Progression-free survival (PFS) of subjects (percentage) who initiate treatment, 
reported as the number who remain alive without progression 5 years after 
treatment.  Subjects withdrawn for treatment-related AEs, or lost to follow-up 
before 5 years, will report as the last date known alive  
3. Incidence of adverse events (not including laboratory abnormalities) while receiving 
treatment and within 30 days, reported by treatment group for severity (as graded by 
NCI CTCAE v5), seriousness (YES/no), and relationship to the study treatments  
4. Incidence of laboratory abnormalities reported by treatment group for severity (as 
graded by NCI CTCAE v5)  
3. 
PARTICIPANT SELECTION 
The Inclusion and Exclusion Criteria are provided on the Participant Eligibility Checklist 
following, which must be completed in its entirety for each subject prior to registration (see 
Section 10.4 Subject Registration).  The checklist may be extracted from this document for 
use in screening potential subjects.  The completed, signed, and dated checklist must be 
retained in the subject’s study file, and the study’s Regulatory Binder.  
Pursuant to Stanford Medicine SOP “Confirmation of Participant Eligibility in Clinical 
Trials,” the treating Physician (investigator);  the Study Coordinator;  and an 
Independent Reviewer will verify that the subject’s eligibility is accurate;  complete;  and 
legible in source records.  A description of the eligibility verification process should be 
included in the EPIC or other Electronic Medical Record progress note.  


 
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Protocol Title: 
A Phase 1B Dose Escalation Trial of human anti-4-1BB agonistic 
antibody Utomilumab (PF-05082566) with ado-trastuzumab-emtansine 
or trastuzumab in patients with HER2-positive advanced breast cancer 
Protocol Number: 
IRB-37299 / BRS0070  
Principal Investigator: 
George W Sledge, Jr, MD 
II. Subject Information: 
Subject Name/ID: 
 
Gender:    
 Male     
 Female 
III. Study Information: 
SRC-Approved 
 IRB-Approved 
 Contract signed 
  
IV. Inclusion / Exclusion Criteria 
Inclusion Criteria (From IRB-approved protocol) 
Yes 
No Supporting Documentation* 
1. History of biopsy-proven HER2-overexpressing 
breast cancer and radiographic evidence of 
metastatic disease, or locally-recurrent unresectable 
disease.  The HER2 status can be determined either 
by immunohistochemistry (IHC) [IHC score, 3+] or 
by fluorescence in situ hybridization (FISH) [as 
defined by HER2/CEP-17 ratio ≥ 2.0, or HER2 copy 
number ≥ 6], or as otherwise defined by 2018 
ASCO/CAP guidelines. 
o Cohort 1 subjects must have received trastuzumab 
and a taxane separately or in combination.  
o Subjects in Cohort 2 (closed January 2020) must 
have received at least 1 prior therapy, including 
ado-trastuzumab emtansine.  
o Subjects who discontinued prior trastuzumab or 
ado-trastuzumab emtansine due to progressive or 
refractory disease are eligible for enrollment.  
 
 
      


 
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Inclusion Criteria (From IRB-approved protocol) 
Yes 
No Supporting Documentation* 
2. Available tumor samples.  For eligibility, if no 
unstained slides remain, stained pathology slides 
may be reviewed at the treating institution.  
However, a tumor sample is required for research 
evaluations per the following (any of Item 1;  
2;  or 3, in order of preference).  
1. A FFPE tumor tissue block from a de novo fresh 
tumor biopsy obtained during screening will be 
requested, though not mandated.  
2. A recently-obtained archival FFPE tumor tissue 
block (or 10 to 15 unstained slides) from a 
primary or metastatic tumor resection or biopsy 
if the following criteria are met:  
A. The biopsy or resection was performed 
within 1 year of enrollment  
OR 
B. The subject has not received any 
intervening systemic anti-cancer 
treatment from the time the tissue was 
obtained and enrolled onto the current 
study.  
OR  
3. Any archival FFPE tumor tissue block (or 
unstained slides) from primary tumor resection 
specimen (if not provided per above).  The 
archival sample may have been collected at any 
time prior to the current study, regardless of any 
intervening therapy.  If an FFPE tissue block 
cannot be provided, a minimum of 10 unstained 
slides (15 preferable) will be acceptable. 
 
 
      
3. Subjects must have evaluable OR measurable 
disease, as defined by RECIST v1.1.  
 
 
      
4. Women or men, age ≥ 18 years old.  
 
 
      
5. Performance status 0 to 1 (by Eastern Cooperative 
Oncology Group [ECOG] scale).  
 
 
      


 
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Inclusion Criteria (From IRB-approved protocol) 
Yes 
No Supporting Documentation* 
6. Laboratory parameters (must satisfy all):  
Absolute neutrophil count (ANC) ≥ 1.5 × 109/L  
   (≥ 1500/µL)  
Platelet count ≥ 100 × 109/L (≥ 100,000/µL)  
Hemoglobin ≥ 9.0 g/dL;  subjects on therapeutic  
   anticoagulation are eligible if there is no bleeding  
   and they are on a stable dose of anticoagulation  
   therapy (eg, on Coumadin with an INR of 2 to 3)  
   for at least 7 days before registration (prior to the  
   start of therapy, or stable heparin or Factor Xa  
   inhibitor dose) 
Serum creatinine ≤ 1.5 × the ULN or calculated  
   creatinine clearance (by Cockcroft-Gault formula)  
   ≥ 60 mL/min  
Aspartate aminotransferase (AST) ≤ 2.5 × ULN   
Alanine aminotransferase (ALT) ≤ 2.5 × ULN  
Bilirubin ≤ 1.5 × ULN  
 
 
      
7. Subjects must not be pregnant or breastfeeding.  
A pregnancy test will be obtained if the subject is a 
woman of child-bearing potential, defined as a 
sexually-mature woman who has not undergone a 
hysterectomy or and/or bilateral oophorectomy or 
who has not been naturally postmenopausal for at 
least 24 consecutive months (ie, who has had menses 
at any time in the preceding 24 consecutive months) 
with 2 pregnancy tests, one at screening, and another 
immediately preceding the initiation of treatment.  
 
 
      
8. Subjects must have signed an informed consent 
document stating that they understand the 
investigational nature of the proposed treatment  
 
 
      
9. Left ventricular ejection fraction determined by 
echocardiogram or multiple-gated acquisition scan 
(MUGA) (cardiac scan) must be 50% or higher  
 
 
      
 


 
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Exclusion Criteria (From IRB-approved protocol) 
 
1. Previously discontinued either trastuzumab or 
ado-trastuzumab emtansine due to intolerance. 
 
 
      
2. Received any other investigational agents within 
30 days of registration. 
 
 
      
3. Central nervous system (CNS) metastases, unless 
previously treated by either radiation therapy and/or 
surgical resection, clinically-stable for at least 60 days 
and on a stable corticosteroid dose of ≤ 4 mg/day 
decadron (or equivalent steroid regimen) for at least 
1 month.  Subjects with a history of CNS metastases 
that are both treated and stably-controlled are eligible 
if all of the following apply:   
o Therapy has been administered (surgery and/or 
radiation therapy);   
o There is no additional treatment planned for brain 
metastases;  
o The subject is clinically-stable;   
o The subject is on a stable corticosteroid dose of 
≤ 4 mg/day decadron (or equivalent steroid 
regimen) for at least 1 month. 
 
 
      
4. Prior malignancy (other than in situ cervical cancer, or 
basal cell or squamous cell carcinoma of the skin), 
unless treated with curative intent and without 
evidence of disease for 3 years or longer 
 
 
      
5. Administration of other prior anticancer therapies 
within 4 weeks of enrollment, except ongoing 
administration of a bisphosphonate drug or 
denosumab as treatment for bone metastasis 
 
 
      
6. Toxicities related to prior anticancer treatment (except 
alopecia) that have not resolved to ≤ Grade 1 
according to common terminology criteria for adverse 
events (CTCAE v5) before registration or prior to start 
of therapy 
 
 
      
7. Currently receiving systemic antibiotic, antiviral, or 
antifungal therapy for the treatment of an active 
infection 
 
 
      


 
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Exclusion Criteria (From IRB-approved protocol) 
 
8. Systemic corticosteroid therapy at doses of greater 
than prednisone 5 mg daily (or dose-equivalent 
chronic steroid regimen) for therapeutic and not 
adrenal replacement indications (maintenance steroid 
use for adrenal insufficiency is permitted).  Acute 
emergency administration, topical applications, 
inhaled sprays, eye drops or local injections of 
corticosteroids are allowed. 
 
 
      
9. History of bleeding diathesis 
 
 
      
10. Any co-morbid medical condition deemed by the 
treating or principal investigator to possibly put the 
subject at significant risk for toxicity. 
 
 
      
11. Subject has known sensitivity to any of the products to 
be administered during dosing 
 
 
      
12. Subject has any kind of disorder that compromises the 
ability of the subject to give written informed consent 
and/or to comply with study procedures 
 
 
      
13. Uncontrolled intercurrent illness including, but not 
limited to, symptomatic congestive heart failure, 
unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit 
compliance with study requirements 
 
 
      
14. History of venous thromboembolism within prior 
6 months.  
 
 
      
15. Subject with reproductive potential who will not agree 
to use, during the study and for 60 days after the last 
dose of utomilumab or 6 months for ado-trastuzumab 
emtansine or trastuzumab 2 highly effective method of 
contraceptive such as:  
o Implants 
o Injectables 
o Intrauterine devices (IUDs) such as copper T or 
levonorgestrel-releasing intrauterine system 
(LNG-IUS) 
o Sexual abstinence 
o Vasectomized partner 
o Condom or occlusive cap (diaphragm or 
cervical/vault cap) supplemented with the use of a 
spermicide during treatment. 
 
 
      


 
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*All subject files must include supporting documentation to confirm subject eligibility.  The method 
of confirmation can include, but is not limited to, laboratory test results, radiology test results, subject 
self-report, and medical record review.   
IV.  Statement of Eligibility 
By signing this form of this trial I verify that this subject is [
 eligible / 
 ineligible] for 
participation in the study. This study is approved by the Stanford Cancer Institute Scientific 
Review Committee, the Stanford IRB, and has finalized financial and contractual agreements 
as required by Stanford School of Medicine’s Research Management Group.   
Treating Physician Signature: 
Date: 
Printed Name: 
 
Secondary Reviewer Signature: 
Date: 
Printed Name: 
 
Stanford Designate Signature: 
Date: 
Printed Name: 
 


 
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3.3. 
Informed Consent Process 
All participants must be provided a consent form describing the study with sufficient 
information for participants to make an informed decision regarding their participation.  
Participants must sign the IRB approved informed consent prior to participation in any study 
specific procedure.  The participant must receive a copy of the signed and dated consent 
document.  The original signed copy of the consent document must be retained in the medical 
record or research file. 
3.4. 
Study Timeline 
It is anticipated that the study will reach primary completion (final subject enrollment and 
treatment) within 48 months from the time the study opens to accrual.  The study is estimated 
to reach completion 60 months from the time the study opens to accrual. 
Treatment with study drugs will continue until completion of 24 cycles of treatment (up to 
about 18 months), confirmed disease progression, subject refusal, unacceptable toxicity, 
whichever occurs first, or the study is prematurely terminated by the investigator, or one of 
the other reasons for subject withdrawal as specified in Section 4.8 will occur. 
4.   
STUDY DESIGN 
This is a parallel cohort, open-label, non-randomized treatment study.  The cohorts are: 
1. Ado-trastuzumab emtansine 3.6 mg/kg IV Q3W plus utomilumab (Cohort 1, with 
utomilumab administered at 20 mg or 100 mg), or 
2. Trastuzumab 6 mg/kg IV Q3W plus utomilumab (Cohort 2, with utomilumab 
administered at 20 mg or 100 mg.  Cohort closed January 2020) 
4.1. 
Starting Dose Selection Strategy 
In the ongoing first-in-human phase 1 study B1641001, utomilumab has been well-tolerated 
up to 10 mg/kg once every 4 weeks with no dose-limiting toxicity. 
However, in order to minimize the potential risk of synergistic toxicity due to the 
combination, a starting dose of utomilumab 20 mg (0.24 mg/kg) [which is 41.6-fold lower 
than the 10 mg/kg dose found to be well-tolerated with no dose-limiting toxicity in protocol 
B1641001] was chosen for this protocol, as this dose is 1) safe, and 2) exposure is adequate 
based on the cumulative data in the B1641001 study. 
The starting dose for ado-trastuzumab emtansine (3.6 mg/kg IV q 3 weeks) in this protocol is 
the full FDA-approved dose for subjects with HER2+ metastatic breast cancer, and the 
starting dose of trastuzumab (6 mg/kg IV q3 weeks) is the full FDA-approved drug dose for 
treatment of HER2+ metastatic breast cancer. 
4.2. 
Criteria for Dose Escalation 
For Cohort 1, utomilumab at escalating doses of 20 mg and 100 mg will be given 
intravenously in combination with the FDA-approved dose and schedule of ado-trastuzumab 
emtansine (3.6 mg/kg IV) every 3 weeks.  On Cycle 1, ado-trastuzumab emtansine will be 
administered on Day 0, followed by utomilumab on Day 1.  On all subsequent cycles (because 
of the known long half-life of ado-trastuzumab emtansine), ado-trastuzumab emtansine and 


 
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utomilumab will be administered on the same day, with utomilumab being administered 
following the end of ado-trastuzumab emtansine infusion.  Initially, 3 subjects will be treated 
at each dose level.  For the first 3 subjects at each utomilumab dose level, there will be a 
minimum 7-day window between the first dose of subject 1 and the first dose of subject 2.  
For all subsequent subjects enrolled in dose-escalation stages, a minimum 72-hour window 
will apply between first doses.  For the expansion cohort combination of ado-trastuzumab 
emtansine plus utomilumab at the RP2D dose, no fixed time interval between subject 
enrollment and treatment need apply. 
As indicated in the Protocol Synopsis Schema section above, it is to note that other more 
complex adaptive trial designs were considered, however as just 2 doses of utomilumab will 
be tested in combination with ado-trastuzumab emtansine or trastuzumab, and as the safety of 
utomilumab IV has been well tolerated to date in combination with other ADCC-inducing 
mAbs (with defined PK), the present dosing scheme has been devised as an efficient means to 
arrive at the RP2D.  Accordingly, the criteria for dose-escalation will be based on a modified 
3+3 dose-escalation procedure (with expansion of the RP2D dose levels to a total of 9 subjects 
to gain further confidence in the RP2D determination). 
However, if a DLT is observed in 1 of the initial 3 treated subjects, 3 additional subjects will 
be enrolled and treated at the same dose level. 
If no further DLT is observed, the next dose level will be opened. 
Subsequent dose levels will not be opened until all subjects entered at the current dose level 
have been treated and observed for at least 21 days after the 1st dose in Cycle 2 is given, and 
the number of DLTs among those subjects in their first two cycles has been determined.  If 
a subject in a cohort drops out of study during the DLT observation period due to reasons 
other than a dose limiting toxicity (eg, progression of disease;  no longer willing to 
participate;  etc), another subject (ie, replacement) will be enrolled. 
Dose-escalation will continue until DLTs are observed in at least 2 of the 3 to 6 subjects 
treated at a dose level, leading to the conclusion that the MTD has been exceeded and thereby 
ending dose-escalation (or until utomilumab 100 mg IV dose cohorts with ado-trastuzumab 
emtansine and trastuzumab are filled).  Doses of utomilumab higher than 100 mg will not be 
tested in either Cohort 1 or Cohort 2, even if the MTD of utomilumab in combination with 
either ado-trastuzumab emtansine or trastuzumab is not exceeded.  If a dose exceeding the 
MTD has been identified, the next lower dose is declared the MTD, provided that 6 subjects 
have already been treated at that dose with 0 or 1.  
DLTs experienced in total.  [3 additional subjects may need to be enrolled at this dose level 
for a total of 6].  If 2 or more subjects are deemed to have DLTs, the dose will be further 
de-escalated and the dosing interval will be adjusted based on the observed DLTs. 
When 6 subjects have been treated at the MTD dose, the MTD dose cohort will be further 
expanded to a total N = 9 subjects in order to further characterize the safety at that dose level.  
If 3 or more subjects at the expanded MTD experienced DLT, the dose will be de-escalated.  
The MTD/RP2D will be defined as the utomilumab dose in combination with standard dose 
ado-trastuzumab emtansine in which no more than 2 of 9 subjects experience DLT.  The 
expansion cohort may be selected at this dose or at a lower dose based on observed clinical 
activity. 


 
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For Cohort 2, Dose Level 1 – Utomilumab 20 mg IV + trastuzumab 6 mg/kg IV every 
3 weeks.  3 subjects will be treated at this dose level.  If no DLT events are recorded, then 
utomilumab dose will be increased to 100 mg (Dose Level 2, below).  If 1 DLT is observed 
amongst the first 3 subjects, then Dose Level 1 will be expanded to 6 subjects.  If no further 
DLTs are observed, then utomilumab will proceed to 100 mg (Dose Level 2).  If 2 (or more) 
DLTs are recorded at Dose Level 1, enrollment in the trastuzumab + utomilumab cohort will 
be terminated.  
Dose Level 2 – Utomilumab 100 mg IV + trastuzumab 6 mg/kg IV every 3 weeks.  3 subjects 
will be dosed initially.  If 1 DLT is observed, Dose Level 2 will be expanded to 6 subjects.  If 
no further DLTs are observed, then utomilumab 100 mg IV + trastuzumab 6 mg/kg IV will be 
expanded to 9 subjects to gain further confidence in the RP2D determination.  If no DLTs are 
observed in the first 3 subjects, then Dose Level 2 will also be expanded to 9 subjects total to 
define the RP2D.  If more than 2 DLTs are recorded in Dose Level 2, then by definition the 
MTD will be exceeded, and dosing will be decreased to utomilumab 20 mg/kg IV, with 
enrollment to the Dose Level 1 cohort to a total of 9 subjects.  If ≤ 2 DLTs are observed in 
9 subjects at Dose Level 1 (utomilumab = 20 mg/kg IV), then utomilumab 20 mg/kg IV in 
combination with trastuzumab 6 mg/kg IV will be the RP2D.  
Due to differences in eligibility between Cohort 1 and Cohort 2, dose-finding and 
dose-escalation are not dependent between cohorts, and may occur at different times.  Accrual 
to both cohorts for dose-finding and dose-escalation will occur in parallel to optimize 
efficiency in dose-finding.  
On Cohort 2, Cycle 1, trastuzumab will be administered on Day 0, followed by utomilumab 
on Day 1.  On all subsequent cycles, trastuzumab and utomilumab will be administered on the 
same day, with utomilumab being administered following the end of trastuzumab infusion.  
Initially, 3 subjects will be treated at each dose level (utomilumab at RP2D).  For the first 
cohort (utomilumab given at RP2D), there will be a minimum 7-day window between the first 
dose of subject 1 and the first dose of subject 2.  For all subsequent subjects enrolled, a 
minimum 72-hour window will apply between first doses.  Utomilumab doses above 100 mg 
will not be tested in this protocol, even if an MTD in combination with trastuzumab 6 mg/kg 
every 3 weeks is not observed.  If a subject in a cohort drops out of study during the DLT 
observation period due to reasons other than a dose-limiting toxicity (eg, progression of 
disease, no longer willing to participate, etc), another subject (ie, replacement) may be 
enrolled.  For reference, the study schema is presented again in Figure 9. 


 
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Figure 9.  Protocol Schema 
4.3. 
Expansion Phase 1B Cohorts 1 and 2 
Utomilumab will be given IV at the RP2D in combination with ado-trastuzumab emtansine 
(Cohort 1) or trastuzumab (Cohort 2, closed January 2020), based on Minimax Simon 2 Stage 
Design.  The null hypothesis that the true objective response rate is 5% will be tested against a 
one-sided alternative.  In 17 response-evaluable subjects (including the 9 subjects already 
treated at the RP2D in the dose-escalation stage), if there are no objective responses the study 
will be terminated.  If 1 or more responses are observed, it will be recommended to conduct a 
future formal phase 2 study of the utomilumab combination under a separate protocol 
document. 
4.4. 
Dose-limiting Toxicity (DLT) Definition 
Severity of AEs will be graded according to CTCAE version 5.  For the purpose of 
dose-escalation, any of the following adverse events occurring during the DLT observation 
period (first 2 Cycles, ie, 6 weeks) that are attributable to one or both study drugs will be 
classified as DLTs: 
Hematologic 
 Grade 4 neutropenia lasting > 7 days 
 Febrile neutropenia, defined as absolute neutrophil count (ANC) < 1000/mm3 with a single 
temperature of > 38.3 degrees C (101 degrees F) or a sustained temperature of ≥ 38 degrees C 
(100.4 degrees F) for more than 1 hour; 


 
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 Grade ≥ 3 neutropenic infection 
 Grade ≥ 3 thrombocytopenia with bleeding 
 Grade 4 thrombocytopenia.  Non-Hematologic: 
 Grade ≥ 3 non-laboratory toxicities, except for nausea, vomiting and diarrhea that has 
been treated and recovered to < Grade 2 within 48 hours. 
 Grade ≥ 3 laboratory abnormalities [other than aspartate aminotransferase/ alanine 
aminotransferase (AST/ALT)] if: 
o Medical intervention is required to treat the subject, or 
o The abnormality leads to hospitalization, or 
o Lasts more than 24 hours 
 Grade 4 AST and ALT increase 
 Criteria for Hy’s Law is met: 
o ALT or AST > 3 × ULN 
o Total bilirubin > 2 × ULN, with no elevation of alkaline phosphatase 
o No other reason for these abnormalities or pre-existing liver disease 
4.5. 
Maximum-tolerated Dose (MTD) Definition 
The MTD estimate is the highest dose associated with the occurrence of DLTs, as 
pre-specified in the DLT Definition section, in < 33% of DLT-evaluable subjects. 
In practice using the modified 3+3 design, the MTD estimate is the dose level at which 0 of 6;  
1 of 6;  or 2 of 9 DLT-evaluable subjects experience a DLT during the first two cycles with 
the next higher dose having at least 2 of 3 to 6 or at least 3 of 9 DLT-evaluable subjects 
experiencing DLTs. 
4.6. 
Recommended Phase 2 Dose (RP2D) Definition 
The recommended phase 2 dose (RP2D) is the dose chosen for further study based on phase 1 
results.  If the MTD proves to be clinically feasible for long term administration in a 
reasonable number of subjects, such dose usually becomes the RP2D.  Further experience 
with the MTD may result in a RP2D dose lower than the MTD. 
4.7. 
Concomitant Medication and Supportive Care Guidelines 
Administration of other prior anticancer therapies within 4 weeks of enrollment, except 
ongoing administration of a bisphosphonate drug or denosumab as treatment for bone 
metastasis, is prohibited.  Additionally, the concurrent use of vitamins or herbal supplements 
should be considered with caution. 
Concomitant treatment considered necessary for the subject’s well-being may be given at 
discretion of the treating physician.  All concomitant medications, blood products, as well as 
interventions (eg, paracentesis, etc) received by subjects from screening until the end of study 
visit will be recorded in the CRF. 


 
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Palliative radiotherapy on study is permitted for the treatment of painful bony lesions 
providing the lesions were known at the time of study entry and the investigator clearly 
indicates that the need for palliative radiotherapy is not indicative of disease progression.  In 
view of the current lack of data about the interaction of utomilumab with radiotherapy, 
utomilumab treatment should be interrupted during palliative radiotherapy, resuming 
utomilumab treatment after recovery to ≤ Grade 1 radiotherapy-related toxicity. 
Primary prophylactic use of granulocyte-colony stimulating factors is not permitted during the 
first two cycles of treatment but they may be used to treat treatment emergent neutropenia as 
indicated by the current American Society of Clinical Oncology (ASCO) guidelines.  
(J Clin Oncol.  2006;24(19):3187-3205). 
Erythropoietin may be used at the investigator’s discretion for the supportive treatment of 
anemia. 
Chronic, systemic corticosteroid use of more than 5 mg/day prednisone (or equivalent 
corticosteroid regimen) for palliative or supportive purpose is not permitted.  Use of short 
course corticosteroids as symptomatic treatment for acute medical conditions may be allowed 
on individual basis, if no acceptable alternatives are available.  Acute emergency 
administration, topical applications, inhaled sprays, eye drops or local injections of 
corticosteroids are allowed. 
4.8. 
Criteria for Removal From Study 
Subjects may withdraw from treatment at any time at their own request, or they may be 
withdrawn at the discretion of the investigator for safety, behavioral, or administrative 
reasons. 
Reasons for subject discontinuation of study treatment may include: 
 
Objective disease progression according to RECIST criteria v1.1; 
 
Global deterioration of health status requiring discontinuation; 
 
Unacceptable toxicity which may also be an adverse event; 
 
Significant protocol violation; 
 
Lost to follow-up; 
 
Subject refused further treatment; 
 
Study terminated by the investigator or Pfizer; 
 
Death; 
 
Pregnancy 
Reasons for subject withdrawal from study follow-up may include: 
 
Completed study follow-up; 
 
Study terminated by the PI or Pfizer; 
 
Lost to follow-up; 
 
Refusal for further follow-up for survival; 
 
Start of an alternative treatment regimen; 
 
Death. 


 
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If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  In any circumstance, every effort should be made to document subject outcome, if 
possible.  The investigator should inquire about the reason for withdrawal, request the subject 
to return for a final visit, and follow-up with the subject regarding any unresolved adverse 
events.  The early termination final visit should include all assessments listed for the End of 
Treatment visit.  If the subject withdraws consent for disclosure of future information, no 
further study specific evaluations should be performed, and no additional data should be 
collected.  The PI may retain and continue to use any data collected before such refusal for 
further follow-up. 
4.9 
Alternatives to study participation 
For patients assigned to the ado-trastuzumab emtansine cohort, the current FDA-approved 
standard of care is single agent ado-trastuzumab emtansine.  For patients assigned to the 
trastuzumab cohort, the current standard of care is trastuzumab plus chemotherapy.  There are 
numerous chemotherapy options commonly used in combination with trastuzumab in this 
clinical setting (eg, vinorelbine, capecitabine, gemcitabine, taxanes, and eribulin).  
5.  
INVESTIGATIONAL AGENT INFORMATION 
5.1  
Physical, Chemical, and Pharmaceutical Properties and Formulation  
Name:  
Utomilumab 
Laboratory Nomenclature:  
PF-05082566 
Molecular Weight:  
145 kDa 
Antibody Type:  
Recombinant fully-human IgG2 monoclonal antibody 
Physical Description:  
Clear to opalescent solution 
5.2  
Formulation of utomilumab Solution for Intravenous administration 
Utomilumab Injection, 10 mg/ml is presented as a sterile solution for intravenous 
administration in a 10 mL clear glass vial with an appropriate stopper and aluminum overseal.  
The formulation contains of the active substance utomilumab in a buffered solution containing 
precedented excipients.  The drug product should be stored at 2 to 8ºC (36-46ºF).  Protect 
from light. 
Each vial contains nominal 100 mg of utomilumab in a 10 mL solution.  To ensure that the 
exact volume can be withdrawn by syringe, there is a small amount of overfill in the vial. 
5.3  
Agent Accountability 
Utomilumab drug product will be supplied by Pfizer.  Utomilumab drug product is a solution 
and should be stored refrigerated at 2 to 8°C.  Utomilumab drug product will be supplied in 
glass vials at a 10 mg/mL concentration and labeled as open supplies.  Each vial is packed in 
an individual carton.  Each vial has a unique container number. 
For packaging and labeling information on ado-trastuzumab emtansine and trastuzumab, refer 
to the most recent version of the local product labeling.  Only qualified personnel who are 
familiar with procedures that minimize undue exposure to them and to the environment will 
undertake the preparation, handling, and safe disposal of investigational and cytotoxic (or 
monoclonal antibody) agents.  Specific preparation and dispensing instructions are provided 
in the Dosage Administration Instruction located in the Study Manual.  Refrigerated 


 
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utomilumab drug product will be equilibrated to ambient temperature before preparation and 
administration. 
5.4  
Drug Storage and Accountability 
Utomilumab will be shipped and stored at a temperature between 2° and 8°C.  
Ado-trastuzumab-emtansine and trastuzumab should be stored according to product 
instructions.  The storage conditions stated in the investigator brochure may be superseded by 
the label storage.  The storage conditions and stability of the reconstituted product are detailed 
in the Dosing Administration Instructions.  If a deviation to the storage condition occurs, 
contact Pfizer. 
The Investigator or an approved representative (eg, research pharmacist) will ensure that all 
investigational product is stored in a strictly controlled, secure area, at appropriate 
temperatures and in accordance with applicable regulatory requirements. 
The Investigator or designated personnel must maintain adequate records documenting the 
receipt, use, loss or other disposition of the investigational product(s).  Pfizer may supply drug 
accountability forms that must be used or may approve use of standard institution forms.  In 
either case, the forms must identify the investigational product, including batch or code 
numbers, and account for its disposition on a subject by subject basis, including specific dates 
and quantities.  The forms must be signed by the individual who dispensed the drug and 
copies must be provided to Pfizer when directed. 
At the end of the trial, Pfizer will provide instructions as to disposition of any unused 
investigational product.  If Pfizer authorizes destruction at the trial site, the Investigator must 
ensure that the materials are destroyed in compliance with applicable environmental 
regulations, institutional policy and any special instructions provided by Pfizer.  Destruction 
must be adequately documented. 
5.5  
Drug Administration 
Subjects will receive doses of utomilumab on Day 1 every 3 weeks (one cycle).  A cycle is 
defined as the time from Day 1 dose to the next Day 1 dose.  If there are no treatment delays, 
a cycle will be 3 weeks in duration.  
An every 3-week schedule of utomilumab (instead of every 4 weeks in prior studies) is 
deliberately chosen for 1) clinical feasibility to match the treatment schedule for 
ado-trastuzumab emtansine in Cohort 1 and trastuzumab in Cohort 2, and 2) to avoid a 
staggered dosing schedule (every 4 week) of utomilumab as compared to the trastuzumab and 
ado-trastuzumab emtansine (which are every 3 weeks), which would add considerable 
complexity to the PK analysis. 
Pre-medication is allowed for all subjects, and may include an antihistamine, an antiemetic, an 
anti-inflammatory agent and/or pain reliever. 
The anticipated duration of utomilumab infusion is 1 hour (± 15 minutes).  The infusion rate 
should be reduced or interrupted in the case of symptoms of infusion reaction, and 
symptomatic treatment administered.  The infusion may be continued at one-half the previous 
rate upon improvement of symptoms.  If symptoms persist or worsen, the infusion should be 
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For the administration of ado-trastuzumab emtansine and trastuzumab, refer to the most recent 
version of the FDA-approved product labeling.  
Ado-trastuzumab emtansine or trastuzumab administration:  Treatment will be 
administered in a 3-week cycle (ie, 21-day cycle), by intravenous infusion.  The first infusion 
of ado-trastuzumab emtansine or trastuzumab on-study will be over 
90 minutes (± 30 minutes), on Cycle 1 Day 0.  Subsequent infusions will be administered over 
30 ± 15 minutes as tolerated (see Appendix 3, Study Schedule of Activities, footnote 16). 
Given the known side effects of ado-trastuzumab emtansine and trastuzumab, and the 
pre-clinical safety data for utomilumab, it is not anticipated that overlapping severe side 
effects will occur.  Subjects will be treated with ado-trastuzumab emtansine (Cohort 1) or 
trastuzumab (Cohort 2) one day prior to the initiation of utomilumab on Cycle 1 to assess for 
ado-trastuzumab emtansine-or trastuzumab-specific side effects.  Subjects should be 
monitored carefully, however, for potential infusion reactions, particularly for the earlier 
cycles of utomilumab.  The safety monitoring as dictated per protocol is consistent with that 
recommended for subjects receiving ado-trastuzumab emtansine or trastuzumab. 
6.  
DOSE MODIFICATIONS 
Every effort should be made to administer study treatment on the planned dose and schedule.  
In the event of significant toxicity dosing may be delayed and/or reduced as described below. 
In the event of multiple toxicities, dose modification should be based on the worst toxicity 
observed.  Subjects are to be instructed to notify Investigators at the first occurrence of any 
adverse symptom. 
Subjects who experience an adverse event meeting the definition of a DLT should be removed 
from treatment. 
Dose modifications may occur in 3 ways: 
 Within a cycle: dose interruption/reduction until adequate recovery during a given 
treatment cycle; 
 Between cycles: next cycle administration may be postponed due to toxicity in the 
previous cycle; 
 In the next cycle: dose reduction based on worst toxicity in the previous cycle. 
Ado-trastuzumab emtansine dose should not be re-escalated after a dose reduction is made. 
The infusion rate of ado-trastuzumab emtansine or trastuzumab should be slowed or 
interrupted as stated in the label if the subject develops an infusion-related reaction.  
Permanently discontinue ado-trastuzumab emtansine or trastuzumab for life-threatening 
infusion-related reactions. 
Management of increased serum transaminases, hyperbilirubinemia, left ventricular 
dysfunction, thrombocytopenia, pulmonary toxicity or peripheral neuropathy may require 
temporary interruption, dose reduction or treatment discontinuation of ado-trastuzumab 
emtansine as per guidelines provided in Tables 2 to 5. 


 
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Table 2.  Recommended Ado-trastuzumab Emtansine (Kadcyla)  
Dose Reduction Schedule for Adverse Events 
Dose Reduction Schedule 
Dose Level 
Starting dose 
3.6 mg/kg 
First dose reduction 
3 mg/kg 
Second dose reduction 
2.4 mg/kg 
Requirement for further dose reduction 
Discontinue treatment 
Hepatotoxicity 
A reduction in the dose of ado-trastuzumab emtansine is recommended in the case of 
hepatotoxicity exhibited as increases in serum transaminases and/or hyperbilirubinemia (see 
Tables 3 and 4). 
Table 3.  Dose Modification Guidelines for Increased Serum Transaminases (AST/ALT) 
 
Table 4.  Dose Modification Guidelines for Hyperbilirubinemia 
 
Permanently discontinue ado-trastuzumab emtansine treatment in subjects with serum 
transaminases > 3 × ULN and concomitant total bilirubin > 2 × ULN. 
Permanently discontinue ado-trastuzumab emtansine in subjects diagnosed with nodular 
regenerative hyperplasia (NRH). 
Thrombocytopenia 
A reduction in dose is recommended in the case of Grade 4 thrombocytopenia (platelets 
< 25,000/mm3 (see Table 5). 


 
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Table 5.  Dose Modification Guidelines for Thrombocytopenia 
 
Pulmonary Toxicity 
Ado-trastuzumab emtansine should be permanently discontinued in subjects diagnosed with 
interstitial lung disease (ILD) or pneumonitis. 
Peripheral Neuropathy 
Ado-trastuzumab emtansine should be temporarily discontinued in subjects experiencing 
Grade 3 or 4 peripheral neuropathy until resolution to ≤ Grade 2. 
Left Ventricular Dysfunction 
Dose Modifications for Left Ventricular Dysfunction 
For symptomatic congestive heart failure, ado-trastuzumab emtansine, trastuzumab and 
Utomilumab will be permanently discontinued and subjects removed from the study.  If the 
left ventricular ejection fraction decreases to less than 50% and is ≥ 10% points from baseline, 
ado-trastuzumab emtansine, trastuzumab, and utomilumab should be held, with repeat LVEF 
assessment within 3 to 4 weeks.  If the LVEF has not recovered to within 10% points from 
baseline, ado-trastuzumab emtansine, trastuzumab and utomilumab will be permanently 
discontinued and subjects removed from the study.  If the LVEF decreases to less than 50%, 
but is within 10% points from baseline and the subject is asymptomatic with respect to cardiac 
signs/symptoms, continue medical treatment with reassessment of the LVEF within 3 weeks. 
Dose Interruptions/Delay 
A new cycle of treatment may begin only if: 
 ANC ≥ 1,000/µL; 
 Platelets count ≥ 75,000/µL; 
 Non-hematologic toxicities have returned to baseline or Grade ≤ 2 severity.  If these 
conditions are not met, treatment must be delayed by 1 week.  If, after a 1-week delay, all 
toxicities have recovered within the limits described above treatment with utomilumab or 
ado-trastuzumab emtansine or trastuzumab, as applicable, can be resumed.  Both study 
drugs should be delayed simultaneously if applicable.  If the subject has not recovered 
after 1 week of delay, treatment may be delayed by 1 more week.  However, initiation of 
the next cycle can only be delayed by a maximum of 2 weeks.  Therefore, if persisting 
toxicity does not allow for the resumption of treatment, the subject will be permanently 
discontinued. 


 
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Dose Reductions 
Subjects who experience a DLT will be removed from the study.  After the first two cycles 
dose reductions may be required based on the worst toxicity experienced in the previous 
cycle.  Subjects experiencing recurrent and intolerable Grade 2 toxicity may resume dosing at 
the next lower dose level once recovery to ≤ Grade 1 or baseline is achieved. 
Dose reduction for utomilumab-related serious adverse events is not allowed.  In such cases 
the subject should discontinue treatment with this drug.  In Cohort 2, no dose reductions of 
trastuzumab will be allowed. 
Once a subject has a dose reduction for a drug-related toxicity, the dose for that drug will not 
be re-escalated.  For subjects requiring more than 2 dose reductions of ado-trastuzumab 
emtansine for treatment-related toxicity, ado-trastuzumab emtansine will be discontinued as 
per the approved package insert.  At the investigator’s discretion, utomilumab may be 
continued until disease progression or cumulative dose-limiting toxicity.  
Infusion-Related Reactions, Hypersensitivity Reactions in Cohort 1  
Treatment with ado-trastuzumab emtansine has not been studied in subjects who had 
trastuzumab permanently discontinued due to infusion-related reactions (IRR) and/or 
hypersensitivity; treatment with ado-trastuzumab emtansine is not recommended for these 
subjects.  Infusion-related reactions, characterized by one or more of the following symptoms 
− flushing, chills, pyrexia, dyspnea, hypotension, wheezing, bronchospasm, and tachycardia 
have been reported in clinical trials of ado-trastuzumab emtansine.  In a randomized 
FDA-registrational trial, the overall frequency of IRRs in subjects treated with 
ado-trastuzumab emtansine was 1.4%.  In most subjects, these reactions resolved over the 
course of several hours to a day after the infusion was terminated.  Ado-trastuzumab 
emtansine treatment should be interrupted in subjects with severe IRR.  Ado-trastuzumab 
emtansine treatment should be permanently discontinued in the event of a life-threatening 
IRR.  Subjects should be observed closely for IRR reactions, especially during the first 
infusion.  One case of a serious, allergic/anaphylactic-like reaction has been observed in 
clinical trials of single-agent ado-trastuzumab emtansine.  Medications to treat such reactions, 
as well as emergency equipment, should be available for immediate use.   
Management of Infusion Reactions, Cohort 2: During the first infusion with trastuzumab, a 
symptom complex most commonly consisting of chills and/or fever was observed in about 
40% of subjects 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.   
ASSESSMENTS 
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described.  However it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator, that may make it unfeasible to 
perform the test.  In these cases the investigator will take all steps necessary to ensure the 


 
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safety and well being of the subject.  When a protocol required test cannot be performed the 
investigator will document the reason for this and any corrective and preventive actions which 
he/she has taken to ensure that normal processes are adhered to as soon as possible.  The IRB 
will be informed of these incidents in a timely fashion, according to governing IRB 
requirements. 
7.1  
Safety Assessment 
Safety assessments will include collection of AEs, SAEs, vital signs and physical 
examination, ECG (12 lead), laboratory assessments, including pregnancy tests and 
verification of concurrent medications. 
7.1.1 Adverse Events 
Assessment of adverse events will include the type, incidence, severity (graded by the 
National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] 
version 5) timing, seriousness, and relatedness. 
Baseline signs and symptoms will be recorded at baseline and then reported as adverse events 
during the trial if they worsen in severity or increase in frequency. 
Adverse events will be collected at every study visit, whether scheduled or unscheduled;  
at end-of-treatment;  and through the Day 60 follow-up.  In addition, if subjects continuing to 
experience toxicity (ie, treatment-related adverse events) following discontinuation of study 
treatment, adverse events will be collected at least every 3 weeks until resolution or 
determination, in the clinical judgment of the Investigator, that no further improvement is 
expected.  Adverse events will not be collected after resolution of treatment-related toxicities 
or 60 days after last dose of study treatment, whichever is later.   
Due to pre-clinical results and human experience with compounds of a similar nature, subjects 
will be assessed at baseline and as medically-indicated by medical history, physical 
examination, and routine laboratory parameters (eg, blood chemistries) for endocrine function 
(including but not limited to TSH, ACTH, and cortisol levels, and may include assessment for 
hypopituitarism and hypoadrenalism) and hepatic events.  Laboratory evaluation of 
hypopituitarism or hypoadrenalism should be considered in subjects who develop signs and 
symptoms that may include unexplained loss of body and facial hair, decreased blood 
pressure, and hyponatremia with hyperkalemia.   In the presence of clinical suspicion, 
laboratory testing should include one or more of the following:  TSH, ACTH, and cortisol 
levels before and 30 to 60 minutes after corticotrophin stimulation.  Referral to an 
endocrinologist should be considered. 
7.1.2 Laboratory Safety Assessments 
Blood and/or urine for hematology, chemistry, coagulation, hepatitis B and C, endocrine 
function (as clinically indicated), urinalysis and pregnancy testing will be collected at the time 
points described in the Schedule of activities (Appendix 3), and analyzed at local laboratories. 
7.1.3 Vital Signs and Physical Examination 
Subjects will have a physical exam to include weight, blood pressure, heart rate, assessment of 
ECOG status and height; height will be measured at baseline only.  Physical examinations will 
be performed at the time points described in the Schedule of activities (Appendix 3). 


 
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7.1.4 ECG Assessments 
Electrocardiogram (ECG): A 12-lead tracing in the supine position will be used for all ECGs 
at each time point (see the Schedule of Activities, Appendix 3).  It is preferable that the 
machine used has a capacity to calculate the standard intervals automatically.  If the QTc is 
prolonged (> 500 msec, ie, ≥ CTCAE Grade 3), then the ECGs should be re-evaluated by a 
qualified person at the site for confirmation as soon as the finding is made, including 
verification that the machine reading is accurate.  If manual reading verifies a QTc of 
> 500 msec, immediate correction for reversible causes (including electrolyte abnormalities, 
hypoxia and concomitant medications for drugs with the potential to prolong the QTc interval) 
should be performed at the discretion of the treating physician.  In addition, repeat ECGs 
should be performed until the QTc interval falls below 500 msec.  If QTc interval reverts to 
less than 500 msec, and in the judgment of Investigator(s) is determined to be due to cause(s) 
other than study drug, treatment may be continued with regular ECG monitoring.  If in that 
timeframe the QTc intervals rise above 500 msec the study drug will be held until the QTc 
interval decreases to ≤ 500 msec.  Subjects will then re-start the study drug at the next lowest 
dose level.  If the QTc interval has still not decreased to < 500 msec after 2-weeks, or if at any 
time a subject has a QTc interval > 515 msec or becomes symptomatic, the subject will be 
removed from the study.  Additional triplicate ECGs may be performed as clinically indicated. 
Prior to concluding that an episode of prolongation of the QTc interval is due to study drug, 
thorough consideration should be given to potential precipitating factors (eg, change in subject 
clinical condition, effect of concurrent medication, electrolyte disturbance) and possible 
evaluation by specialist. 
If subject experiences a cardiac or neurologic AE (specifically syncope, dizziness, seizures, or 
stroke), an ECG should (ideally) also be obtained at the time of the event. 
7.2  
Tumor Response Assessments 
Tumor assessments will include all known or suspected disease sites.  Imaging may include 
chest, abdomen and pelvis CT or MRI scans;  brain CT or MRI scan for subjects with known 
or suspected brain metastases;  bone scan;  PET scan;  CT/PET scan;  and/or bone x-rays for 
subjects with known or suspected bone metastases.  
During screening period within 28 days of Cycle 1 Day 0, tumor assessment is required using 
CT scan with contrast (chest, abdomen, + pelvis), plus radionuclide bone scan or CT/PET 
with contrast.  If central nervous system (CNS) metastasis are present, CNS imaging is 
required by CT or MRI.17  
The same imaging technique used to characterize each identified and reported lesion at 
baseline should ideally be employed in the following tumor assessments.  However, in certain 
clinical circumstances (eg, IV contrast allergy or nephrotoxicity from IV contrast), the most 
suitable imaging modality for an individual patient may be used at the discretion of the 
treating physician.  
Antitumor activity will be assessed through radiological tumor assessments conducted at 
baseline, during treatment as specified in the Schedule of Activity (Appendix 3), whenever 
disease progression is suspected (eg, symptomatic deterioration), and at the time of 
withdrawal from the study (if not done in the previous 6 weeks).  Subjects will be followed up 


 
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to 6 months from the date of the last dose of the study drug, with follow-up ending at death;  
disease progression;  or initiation of a new anticancer therapy.  During this follow-up period, 
subjects will have disease assessments performed every 9 weeks (± 7 days).  
Utomilumab is thought to stimulate patients’ immune systems to attack their tumors, rather 
than to have a direct and immediate effect on tumor cells.  In addition, drugs with a similar 
mechanism have been observed to have a delayed effect on tumors.  It is possible that new 
lesions may appear early after treatment begins, before an effective immune response is 
induced.  In addition, it is postulated that there may be initial increase in size of lesions due to 
infiltration of inflammatory cells, which is later followed by tumor regression.  In some cases, 
this inflammation could make an undetectable lesion increase in size so that it appears to be a 
new lesion.  In addition, subjects may have mixed responses, in which some lesions respond 
while other lesions progress or new lesions appear.  There may be cases where, in the 
judgment of the Sponsor-investigator, a patient with a mixed response appears to be deriving 
benefit from the treatment.  In such cases, at the discretion of the Sponsor-investigator, 
subjects may continue treatment until clinical benefit is no longer present in the opinion of the 
Investigator.  
Assessment of response will be made using RECIST v1.1 (for solid tumors). 
All subjects’ files and radiologic images must be available for source verification and for 
potential peer review. 
7.3  
Pharmacokinetic Assessment 
PK samples will be collected as specified in the Schedule of Activity (Appendix 3), and 
assayed for utomilumab, ado-trastuzumab emtansine or trastuzumab using a validated 
analytical assay.  Analysis of samples from subjects who received utomilumab and 
trastuzumab is optional.  Details regarding the collection, processing, storage and shipping of 
the blood samples will be provided in the Laboratory Manual. 
All efforts will be made to obtain the pharmacokinetic samples at the scheduled nominal time 
relative to dosing.  However, samples obtained within 10% of the nominal time (eg, within 
± 6 minutes of a 60-minute sample) will be considered protocol compliant, and the exact time 
of the sample collection noted on the CRF. 
Wherever possible or applicable, blood samples for utomilumab concentrations should be 
collected at as close to the same time a pharmacodynamic biomarker samples or tumor biopsy 
is collected. 
7.4  
Immunogenicity Assessment 
Blood samples will be collected as specified in the Schedule of Activity (Appendix 3), and 
assayed for anti-drug antibodies (ADA) including, anti-utomilumab, and 
anti-ado-trastuzumab-emtansine or anti-trastuzumab using a validated analytical method.  
Analysis of samples from subjects who received utomilumab and trastuzumab is optional.  
Samples that are positive for ADA may also undergo characterization for neutralizing 
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7.5  
Pharmacodynamic Assessments 
7.5.1.  Blood for Immunomodulation/Cytokine Release Biomarkers 
Blood will be analyzed for immune-related biomarkers that may include TNFα;  IFNγ;  IL10;  
IL-8;  IL-6;  IL-4;  IL-2;  IL-1b;  IL-12p70;  sFasL;  CRP;  sCD25;  CXCL9;  CXCL10;  and 
Neopterin, etc.  The specific biomarkers in the immunomodulation/cytokine release biomarker 
panel is subject to change based upon technical updates to the panel made by the Stanford 
Human Immune Monitoring Core Facility.  Analysis of samples from subjects who received 
utomilumab and trastuzumab is optional.  
7.5.2.  Pharmacodynamic Assessment of Lymphocyte Subpopulations 
Blood and available tumor will be analyzed for biomarkers indicative of key immune cell 
populations, including T-cell, NK cells, and B-cells.  Analysis of samples from subjects who 
received utomilumab and trastuzumab is optional.   
7.5.3.  T-cell receptor assessment 
Blood and available tumor will be collected for future analysis of T-cell receptor frequencies 
using targeted sequencing.  Analysis of samples from subjects who received utomilumab and 
trastuzumab is optional.   
7.6  
Tumor Biopsies 
Tumor biopsies will be requested, though not mandated, pre-treatment and after at least one 
dose of utomilumab (as clinically feasible) for CD8+ T-cells and other markers of tumor 
infiltrating lymphocytes, such as CD3;  CD4;  PD-1;  4-1BB;  FoxP3;  and PD-L1. 
8.   
ADVERSE EVENT REPORTING 
Adverse events will be graded according to CTCAE v5.  Both Serious and Non-Serious 
Adverse Events will be clearly noted in source documentation and listed on study-specific 
Case Report Forms (CRFs).  The Principal Investigator or designee will assess each Adverse 
Event (AE) to determine whether it is unexpected according to the Informed Consent, 
Protocol Document, or Investigator’s Brochure, and related to the investigation.  All Serious 
Adverse Events (SAEs) will be tracked until resolution, or until 30 days after the last dose of 
the study treatment. 
SAEs CTCAE Grade 3 and above, and all subsequent follow-up reports will be reported to the 
Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) using the study 
specific CRF regardless of the event’s relatedness to the investigation.  Following review by 
the DSMC, events meeting the IRB definition of “Unanticipated Problem” will be reported to 
the IRB using eProtocol within 10 working days of DSMC review, or within 5 working days 
for deaths or life-threatening experiences. 
All observed or volunteered adverse events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 
For all adverse events, the local Principal Investigator (treating physician) must pursue and 
obtain information adequate both to determine the outcome of the adverse event and to assess 
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notification to the Sponsor-investigator (IND-holder or designate).  For all adverse events, 
sufficient information should be obtained by the local Principal Investigator to determine the 
causality of the adverse event.  The local Principal Investigator and/or the 
Sponsor-investigator will assess causality.  Follow-up by the local Principal Investigator may 
be required until the event or its sequelae resolve or stabilize at a level acceptable to the 
investigator.  
8.1  
Reporting Period 
For serious adverse events, the active reporting period begins from the time that the subject 
provides signed informed consent, which is obtained prior to the subject’s participation in the 
study, ie, prior to undergoing any study-related procedure and/or receiving investigational 
product, through and including 28 calendar days after the last administration of the 
investigational product or including 60 calendar days after the last administration of the 
investigational product if no other therapy is administered.  Should an investigator be made 
aware of any serious adverse event occurring any time after the active reporting period, it 
must be promptly reported. 
Adverse events (serious and non-serious) should be recorded on the CRF from the time the 
subject has taken at least one dose of study treatment through last subject visit.  
If a subject begins a new anticancer therapy, the adverse event reporting period for 
non-serious adverse events ends at the time the new treatment is started.  Death must be 
reported if it occurs during the serious adverse event reporting period after the last dose of 
investigational product, irrespective of any intervening treatment. 
8.2  
Definition of an Adverse Event 
An adverse event is any untoward medical occurrence in a clinical investigation subject 
administered a product or medical device; the event need not necessarily have a causal 
relationship with the treatment or usage.  Examples of adverse events include but are not 
limited to: 
 Abnormal test findings; 
 Clinically significant symptoms and signs; 
 Changes in physical examination findings; 
 Hypersensitivity/allergy; 
 Drug abuse; 
 Drug dependency. 
Additionally, they may include the signs or symptoms resulting from: 
 Drug overdose; 
 Drug withdrawal; 
 Drug misuse; 
 Drug interactions; 
 Extravasations; 
 Exposure during pregnancy; 


 
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 Exposure via breastfeeding; 
 Medication error. 
Worsening of signs and symptoms of the malignancy under study should be reported as 
adverse events in the appropriate section of the CRF.  Disease progression assessed by 
measurement of malignant lesions on radiographs or other methods should not be reported as 
adverse events. 
8.3  
Abnormal Test Findings 
The criteria for determining whether an abnormal objective test finding should be reported as 
an adverse event are as follows: 
 Test result is associated with accompanying symptoms; and/or 
 Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or 
 Test result leads to a change in study dosing (outside of protocol-stipulated dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or 
 Test result is considered to be an adverse event by the investigator or sponsor. 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an adverse event.  Any abnormal test result that is determined to be an error does 
not require reporting as an adverse event. 
8.4  
Serious Adverse Events 
A serious adverse event is any untoward medical occurrence at any dose that: 
 Results in death; 
 Is life-threatening (immediate risk of death); 
 Requires in-patient hospitalization or prolongation of existing hospitalization; 
 Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions); 
 Results in congenital anomaly/birth defect; 
Progression of the malignancy under study (including signs and symptoms of progression) 
should not be reported as a serious adverse event unless the outcome is fatal within the safety 
reporting period.  Hospitalization due to signs and symptoms of disease progression should 
not be reported as serious adverse event.  If the malignancy has a fatal outcome during the 
study or within the safety reporting period, then the event leading to death must be recorded as 
an adverse event and as a serious adverse event with CTCAE Grade 5.  Medical and scientific 
judgment is exercised in determining whether an event is an important medical event.  An 
important medical event may not be immediately life-threatening and/or result in death or 
hospitalization.  However, if it is determined that the event may jeopardize the subject or may 
require intervention to prevent one of the other adverse event outcomes, the important medical 
event should be reported as serious.  Examples of such events are intensive treatment in an 


 
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emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that 
do not result in hospitalization; or development of drug dependency or drug abuse. 
8.5  
Causality Assessment 
The investigator’s assessment of causality must be provided for all adverse events (serious 
and non-serious); the investigator must record the causal relationship in the CRF, as 
appropriate, and report such an assessment in accordance with the serious adverse reporting 
requirements if applicable.  An investigator’s causality assessment is the determination of 
whether there exists a reasonable possibility that the investigational product caused or 
contributed to an adverse event; generally the facts (evidence) or arguments to suggest a 
causal relationship should be provided.  If the investigator does not know whether or not the 
investigational product caused the event, then the event will be handled as “related to 
investigational product” for reporting purposes.  If the investigator's causality assessment is 
"unknown but not related to investigational product", this should be clearly documented on 
study records. 
In addition, if the investigator determines a serious adverse event is associated with study 
procedures, the investigator must record this causal relationship in the source documents and 
CRF, as appropriate, and report such an assessment in accordance with the serious adverse 
event reporting requirements. 
8.6  
RISKS ASSOCIATED WITH TRASTUZUMAB 
Note:  Cohort 2, utomilumab plus trastuzumab, was closed in January 2020.  
Trastuzumab is a recombinant monoclonal antibody that binds specifically and with high 
affinity to the extracellular domain of HER2.  Trastuzumab has been shown to inhibit the 
proliferation of human tumor cells overexpressing HER2 both in vitro and in vivo. 
The clinical benefit of trastuzumab in women with MBC has been demonstrated in two 
pivotal studies. 
A phase 2 trial (H0649g) assessed the activity of single-agent trastuzumab in 222 women with 
HER2-overexpressing MBC with progressive disease after one or more chemotherapy 
regimens (Cobleigh, et al, 1999).  An independent response evaluation committee identified 8 
complete and 26 partial responses, for an objective response rate of 15% in the intent-to-treat 
population (95% confidence interval [CI]: 11% to 21%).  The median duration of response 
was 9.1 months, and the median duration of survival was 13 months.  The most common 
adverse events, which occurred in approximately 40% of subjects, were mild to moderate 
infusion-associated fever and/or chills.  The most clinically significant event was cardiac 
dysfunction, which occurred in 4.7% of subjects. 
An open-label, randomized, phase 3 study (H0648g) in 469 subjects with HER2-positive 
MBC was conducted to evaluate the efficacy of trastuzumab in combination with 
chemotherapy as first-line treatment.  Subjects who were anthracycline-naïve were 
randomized to receive either anthracycline plus cyclophosphamide (AC) or trastuzumab plus 
AC.  Subjects who had received prior anthracyclines in the adjuvant setting were randomized 
to receive either paclitaxel or trastuzumab plus paclitaxel.  As determined by an independent 
response evaluation committee, trastuzumab prolonged median time to disease progression 
from 4.6 months to 7.4 months (p < 0.001), improved the overall response rate (complete and 


 
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partial responses) from 32% to 50% (p < 0.001), and increased median duration of response 
from 6.1 to 9.1 months (p < 0.001).  Compared to chemotherapy alone, the addition of 
trastuzumab significantly lowered the incidence of death at one year from 33% to 22% 
(p = 0.008) and increased median overall survival 24% from 20.3 months to 25.1 months 
(p = 0.046) (Slamon, et al, 2001).  The observed survival advantage remained despite 
crossover of 66% of subjects initially randomized to chemotherapy alone who elected to 
receive trastuzumab upon disease progression (Tripathy, et al, 2000).  Fever/chills were 
observed with the initial trastuzumab infusion in approximately 25% of subjects.  Class III or 
IV cardiac dysfunction was observed in 16% of the trastuzumab + AC subgroup; increasing 
age was an associated risk factor for the development of cardiotoxicity in this treatment cohort 
(Slamon, et al, 2001). 
Based on these data, trastuzumab was approved by the US Food and Drug 
Administration (FDA) for use in HER2-overexpressing MBC in combination with paclitaxel 
for first-line treatment and as a single agent for patients failing prior chemotherapy for 
metastatic disease. 
Trastuzumab is also currently approved in the early breast cancer setting. 
See the trastuzumab (Herceptin®) prescribing information for additional information. 
8.7  
RISKS ASSOCIATED WITH ADO-TRASTUZUMAB EMTANSINE  
The following summarizes the experience with ado-trastuzumab emtansine in multiple breast 
cancer studies to date.  The usual dose used in the studies was 3.6 mg/kg every 3 weeks.  
Trastuzumab emtansine has demonstrated a favorable toxicity and tolerability profile to date 
across multiple studies. 
In a phase 1, TDM3569g, trastuzumab emtansine was administered every 3 weeks.  The MTD 
of trastuzumab emtansine administered every 3 weeks was 3.6 mg/kg.  DLTs consisted of 
Grade 3 and 4 thrombocytopenia that prevented retreatment in 2 of 3 subjects treated at 
4.8 mg/kg on the every-3-week schedule.  Grade ≥ 2 adverse events at the MTD were 
infrequent and manageable.  The most common adverse events (≥ 25% incidence) seen in this 
study were thrombocytopenia, fatigue, nausea, anemia, constipation, headache, increased liver 
function tests, and cough.  Every-3-week trastuzumab emtansine schedules are well tolerated 
and associated with significant clinical activity.  In addition, the phase 2 studies, TDM4258g 
and TDM4374g, have shown similar tolerability of trastuzumab emtansine at a dose of 
3.6 mg/kg administered every 3 weeks. 
Reversible thrombocytopenia has been commonly observed in completed and ongoing studies 
with trastuzumab emtansine.  Most events were Grade 1 or 2;  with Grade 3 or 4 
thrombocytopenia has been observed less commonly.  The incidence of Grade 1 
thrombocytopenia gradually increased over successive cycles; however, there was no increase 
in the proportion of Grade 3 abnormalities.  The number of subjects who experienced platelet 
count recovery to normal levels by Day 1 of the subsequent cycle decreased with successive 
cycles, suggesting a modest cumulative effect of trastuzumab emtansine on platelet count.  
There was no clear association between thrombocytopenia and severe hemorrhagic events; 
however, the use of platelet transfusions has been reported. 


 
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Transient and reversible increases in serum AST and ALT have been observed across the 
trastuzumab emtansine studies.  Grade 1 and 2 events have been observed frequently; 
Grade 3 to 4 events have been observed much less commonly.  The incidence of increased 
AST was substantially higher than that for ALT.  Increases in AST and ALT were commonly 
observed by Day 8 of each cycle and generally returned to baseline by Day 21.  The 
proportion of subjects with Grade 1 and 2 increases in transaminases increased with 
successive cycles; however, no increase in the proportion of Grade 3 abnormalities over time 
was observed.  To date, there have been no cases meeting Hy’s Law criteria for drug-induced 
liver injury caused by trastuzumab emtansine.  Although significant hepatotoxicity has rarely 
been seen in clinical trials with trastuzumab emtansine to date, the relationship to trastuzumab 
emtansine has not been established.  Nevertheless, severe liver injury remains an important 
potential risk. 
Infusion-related reactions are known to occur with the administration of monoclonal 
antibodies and have been reported with trastuzumab emtansine.  Infusion reaction adverse 
events occurred rarely and were mostly Grade 1 or 2.  Non-specific symptoms that occurred 
on the first day of trastuzumab emtansine infusion that could be associated with an infusion 
reaction included fatigue;  nausea;  chills;  pyrexia;  and less commonly, headache;  
hypertension;  vomiting;  and cough. 
Pneumonitis has been rarely reported with trastuzumab emtansine.  Signs, symptoms, and 
clinical findings include dyspnea, cough, fatigue, and pulmonary infiltrates.  There were no 
fatalities among the cases of pneumonitis reported with trastuzumab emtansine. 
In clinical trials with trastuzumab emtansine, peripheral neuropathy has been reported, mainly 
as Grade 1 toxicity.  Hypokalemia and decreases in serum potassium have been reported in 
completed and ongoing studies with trastuzumab emtansine.  Most of these adverse events 
were Grade 1 or 2. 
Although significant cardiac events have been infrequent in clinical trials with trastuzumab 
emtansine to date, severe cardiotoxicity remains an important potential risk.  Treatment with 
trastuzumab, a component of trastuzumab emtansine, has resulted in subclinical and clinical 
cardiac failure manifesting as CHF, decreased LVEF, and cardiac death.  The incidence and 
severity of cardiac dysfunction was highest in subjects who received trastuzumab concurrently 
with anthracycline-containing chemotherapy regimens.  Cardiotoxicity, manifesting as a 
decline in left ventricular ejection fraction (LVEF) or congestive heart failure (CHF), is being 
closely monitored in the current study.  Rare cases of Grade 3 cardiac dysrhythmias have been 
reported among subjects receiving trastuzumab emtansine, although a direct relationship to 
study drug remains unclear. 
Given the potential for trastuzumab emtansine, and trastuzumab to cause cardiac toxicity, only 
subjects without significant cardiac history, with acceptable anthracycline exposure, and with 
an LVEF determined to be ≥ 50% by screening ECHO or MUGA scan are eligible for 
participation in this study.  Repeat ECHO or MUGA scans will be performed at baseline and 
the beginning of Cycle 5 and then every 4 cycles thereafter, using the same noninvasive 
monitoring technique each time, to determine if therapy should be held or discontinued in 
asymptomatic subjects on the basis of local assessment of declines in LVEF.  Any subject 
with symptomatic cardiac dysfunction or a significant decline in LVEF as detected by 
noninvasive cardiac imaging will discontinue all study treatment but will continue to be 


 
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followed for 30 days for adverse events and serious adverse events and every 6 weeks for 
disease progression until the initiation of another anti-cancer therapy, subject- or 
investigator-initiated withdrawal from the study, or study termination. 
8.8  
Infusion-Related Symptoms with Hypersensitivity Reactions 
Infusion-related reactions consisting of fever and/or chills have been observed in ≤ 40% of 
patients during their first infusions of either trastuzumab or ado-trastuzumab emtansine.  The 
symptoms have usually been mild to moderate and controlled with acetaminophen, 
diphenhydramine, or meperidine.  These symptoms are uncommon with subsequent infusions.  
However, in the post-approval setting, more severe adverse reactions to trastuzumab have 
been reported.  These have been categorized as hypersensitivity reactions (including 
anaphylaxis), infusion reactions, and pulmonary events.  In rare cases, the reaction culminated 
in a fatal outcome. 
Administration of ado-trastuzumab emtansine, trastuzumab and utomilumab will be 
performed in a setting with emergency equipment and staff who are trained to monitor and 
respond to medical emergencies.  Subjects will be monitored during each study medication 
infusion, for 60 minutes after the first infusion, and for 30 minutes after subsequent infusions 
in the absence of infusion-related adverse events.  If infusion-associated symptoms occur, the 
subject will be monitored until symptoms completely resolve or are considered by the 
investigator to be clinically insignificant. 
Subjects who experience infusion-related symptoms during the administration of 
ado-trastuzumab emtansine, trastuzumab or utomilumab may be pre-medicated for subsequent 
infusions.  Subjects who experience a Grade ≥ 3 allergic reaction or acute respiratory distress 
syndrome will discontinue all study treatment but will continue to be followed for 30 days for 
adverse events and serious adverse events and every 6 weeks for disease progression until the 
initiation of another anti-cancer therapy, subject- or investigator-initiated withdrawal from the 
study, or the study termination. 
8.9  
RATIONALE FOR CONTINUED DOSING 
Subjects who meet the criteria for ongoing clinical benefit will be allowed to continue study 
treatment in the absence of disease progression, unacceptable toxicity, or the initiation of 
other anti-cancer therapy, unless the study is terminated early for one of the reasons described 
in Sections 4.8 and 11.  
9.   
CORRELATIVE/SPECIAL STUDIES 
9.1  
BIOMARKERS 
Serum and intratumoral biomarkers linked to immunomodulation and cytokine release, 
exploratory PD biomarkers expressed by PBMC and intratumoral lymphocytes, markers of 
T- and NK-cell phenotype, quantitation of T-cell receptor sequences, and tumor biopsy for 
analysis of exploratory mechanistic biomarkers such as IHC assessment of tumor-infiltrating 
lymphocytes and quantitation of T-cell receptor sequences will be collected as indicated in the 
Schedule of Activity (Appendix 3).  A more detailed accounting of the biomarker 
collection/analysis is provided in Appendix 5. 


 
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10.   
REGULATORY CONSIDERATIONS 
Throughout this document, reference to the “Sponsor-investigator” includes designates.  
Sponsor-investigator retains all defined responsibilities of the IND-holder, unless specifically 
delegated or transferred.  
10.1  Institutional Review of Protocol 
The protocol, the proposed informed consent and all forms of participant information related 
to the study (eg, advertisements used to recruit participants) will be reviewed and approved by 
the Stanford IRB and Stanford Cancer Institute Scientific Review Committee (SRC).  The 
Protocol Director will disseminate the protocol amendment information to all participating 
investigators. 
One version of the protocol document should be used at all times.  Prior to implementation, 
the Stanford IRB and SRC will prospectively approve of any amendment to the protocol, 
except where necessary to eliminate an immediate hazard(s) to trial subjects.  With the 
exception of actions to protect the safety and welfare of human subjects, any changes to the 
protocol will be submitted as a modification to the IRBs of record for the clinical site, and will 
be approved by the IRB of record prior to implementation.   
10.4 
Subject Registration 
Subjects may be registered to participate in this study when they have confirmed to meet all 
eligibility requirements (see Eligibility Criteria in Section 3 Participant Selection), and that 
eligibility has been reviewed (Eligibility Triple-check, see Eligibility Checklist in 
Appendix 6).  
All study participants will be entered into OnCore. 
10.5  Data and Safety Monitoring Plan 
The Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) will be the 
monitoring entity for this study.  The DSMC will audit study-related activities approximately 
once per year to determine whether the study has been conducted in accordance with the 
protocol;  local standard operating procedures;  FDA regulations;  and Good Clinical 
Practice (GCP).  This may include review of the following types of documents:  regulatory 
binders, case report forms, eligibility checklists, and source documents.   
In addition, the DSMC will regularly review serious adverse events and protocol deviations to 
ensure the protection of human subjects.  Results of the DSMC audit will be communicated to 
the IRB and the appropriate regulatory authorities at the time of continuing review, or in an 
expedited fashion, as needed.   
10.6  Data Management Plan 
The Principal Investigator, or his/her designee, will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study.  
Study-specific Case Report Forms (CRFs) will be created in the Online Collaborative 
Research Environment (OnCore).  


 
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All electronic data systems and devices should maintain a security system that prevents 
unauthorized access.  All participants must be registered in the OnCore database, allowing the 
Stanford SRC to judge the aggregate accrual and stopping rules for the study.  
10.7 Ethical Conduct of the Study 
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Patients (Council for International Organizations of Medical 
Sciences 2002), Guidelines for Good Clinical Practice (International Conference on 
Harmonization 1996), and the Declaration of Helsinki (World Medical Association 2008). 
In addition, the study will be conducted in accordance with the protocol, the International 
Conference on Harmonization guideline on Good Clinical Practice, and applicable local 
regulatory requirements and laws. 
11.   
STUDY DISCONTINUATION CRITERIA 
Premature termination of this study may occur because of a regulatory authority decision, 
change in the opinion of the IRB/IEC, drug safety problems, or at the discretion of 
utomilumab manufacturer Pfizer.  In addition, Pfizer retains the right to discontinue 
development of utomilumab at any time. 
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
Sponsor-investigator.  As directed by Pfizer, all study materials must be collected and all 
CRFs completed and submitted to the Sponsor-investigator to the greatest extent possible. 
12.   
Publications by Investigators 
To ensure against inadvertent disclosure of Confidential Information or unprotected 
Inventions, the Sponsor-investigator will provide Pfizer an opportunity to review any 
proposed publication or other type of disclosure before it is submitted or otherwise disclosed.   
The Sponsor-investigator will provide manuscripts, abstracts, or the full text of any other 
intended disclosure (poster presentation, invited speaker or guest lecturer presentation, etc) to 
Pfizer at least 30 days before they are submitted for publication or otherwise disclosed.  If any 
patent action is required to protect intellectual property rights, the Sponsor-investigator agrees 
to delay the disclosure for a period not to exceed an additional 60 days.  The 
Sponsor-investigator will, on request, remove any previously undisclosed Confidential 
Information (other than the Study results themselves) before disclosure. 
13.   
DATA ANALYSIS/STATISTICAL METHODS 
13.1  Analysis Sets 
All clinical research data generated by this protocol will be captured in electronic case report 
forms (CRFs) generated using REDCap software.   
1.  Full Analysis Set 
The full analysis set includes all enrolled subjects. 


 
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2.  Safety Analysis Set 
The safety analysis set includes all enrolled subjects who receive at least one dose of study 
medication. 
3.  DLT Evaluable Set 
All enrolled subjects who are eligible, receive study treatment and who either experience DLT 
during the first 2 cycles, or complete the 2-cycle observation period.  Subjects who are lost to 
follow-up before completion of first 2 cycles due to reasons unrelated to treatment related 
adverse events are not evaluable for DLT. 
4.  Response Analysis Set 
All enrolled subjects who are eligible for the study and receive study treatment, have adequate 
baseline tumor assessments and at least 1 on-study tumor assessment.  Subjects who are 
treated and removed from study prior to on-study tumor assessment because of disease 
progression will be considered evaluable for efficacy and counted as failures. 
5.  Pharmacokinetic/Immunogenicity Sets 
The pharmacokinetic/ADA concentration population is defined as all enrolled subjects who 
have been treated and have at least one post-dose concentration measurement of either 
utomilumab or ado-trastuzumab emtansine or trastuzumab. 
6.  Biomarker Analysis Set 
Treated subjects who have baseline and at least 1 on-study biomarker assessment. 
13.2  Statistical Methods and Sample Size Determination 
Overall study population is up to 30 subjects, to achieve 25 evaluable subjects. 
Statistical analyses of this non-randomized, phase 1B study will be primarily descriptive in 
nature.  Formal statistical methods will not be used to determine the number of subjects per 
cohort in this phase 1B study.  Summary statistics for discrete variables will be provided as 
frequencies and for continuous variables as the mean, standard deviation, median, and ranges.  
In Cohort 1 Expansion, utomilumab will be given IV at the RP2D (utomilumab 100 mg IV) in 
combination ado-trastuzumab emtansine  up to a total of 17 evaluable subjects who received 
utomilumab plus ado-trastuzumab emtansine (up to 5 inevaluable subjects may be replaced).  
Cohort 2 (utomilumab plus trastuzumab) was closed in January 2020 with 5 total subjects 
enrolled.  If 1 or more responses are observed, it will be recommended to conduct a future 
formal phase 2 trial under a separate protocol.  
13.2.1 Accrual Considerations 
There are approximately 600 new breast cancer patients seen annually at the Stanford Cancer 
Institute.  It is estimated that half of these cases are metastatic and 20% are HER2-positive.   
13.3  Efficacy Analysis 
Tumor response will be presented in the form of subject data listings that include, but are not 
limited to, tumor type, received (maximum) dose, overall tumor response at each visit, and 
best overall response.  In addition, disease progression date, death date, date of first response, 


 
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and last tumor assessment date will be listed, together with DR and PFS for the expansion 
cohort.  Kaplan-Meier plot will be created for DR, TTR and PFS in the expansion cohort. 
13.4  Analysis of Pharmacokinetics and Pharmacodynamics 
13.4.1 Analysis of Pharmacokinetics of Study Drugs 
Ctrough and Cmax for utomilumab and ado-trastuzumab emtansine or trastuzumab will be 
summarized descriptively (n, mean, SD, CV, median, minimum, maximum, geometric mean, 
its associated CV, and 95% confidence interval) by dose, cycle, and day. 
Dose normalized parameters (eg, Cmax, Ctrough) will be reported as appropriate. 
The trough concentrations for utomilumab and ado-trastuzumab emtansine or trastuzumab 
will be plotted for each dose using a box whisker plot by cycle and day in order to assess the 
attainment of steady state. 
13.4.2.  Analysis of Immunogenicity Data of Study Drugs 
ADA/neutralizing antibody (Nab) data will be listed and summarized for each dosing interval 
for utomilumab, ado-trastuzumab emtansine, or trastuzumab.  The percentage of subjects with 
positive ADA and neutralizing antibodies each will be summarized by dose.  For subjects with 
positive ADA, the magnitude (titer), time of onset, and duration of ADA response may also be 
described, if data permit.  The effect of ADA on utomilumab, ado-trastuzumab emtansine or 
trastuzumab concentrations will be evaluated if data permit. 
13.4.3.  Analysis of Biomarker Endpoints 
For CD8 and HER-2 as wells other exploratory biomarkers in tumor biopsy, summary 
statistics (eg, the mean and standard deviation, median, and minimum/maximum levels of 
continuous, and frequencies and percentages of categorical biomarker measures) will be 
determined at baseline and post-treatment as appropriate.  For each pair of specimens, the 
percent change from baseline of these same parameters will also be calculated. 
Data from biomarker assays may be analyzed using graphical methods and descriptive 
statistics such as linear regression, t-test, and analysis of variance (ANOVA).  The statistical 
approach will examine correlations of biomarker results with pharmacokinetic parameters and 
measures of anti-tumor efficacy. 
13.4.4.  Population Pharmacokinetic Analysis or Pharmacokinetic/Pharmacodynamic 
(PK/PD) Modeling 
Pharmacokinetic and pharmacodynamic data from this study may be analyzed using modeling 
approaches and may also be pooled with data from other studies to investigate any association 
between utomilumab and ado-trastuzumab emtansine/trastuzumab exposure and biomarkers 
or significant efficacy/safety endpoints.  The results of these analyses, if performed, may be 
reported separately. 


 
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13.5  Safety Analysis 
13.5.1 Analysis of the Primary Endpoint 
DLT is the primary endpoint of the study.  Analyses of DLT are based on the DLT-evaluable 
set.  The occurrence of DLTs and Adverse Events constituting DLTs will be summarized and 
listed per dose for subjects. 
13.5.2 Analysis of Secondary Safety Endpoints 
Adverse Events 
Adverse Events (AEs) will graded by the investigator according to the Common Terminology 
Criteria for Adverse Events (CTCAE) version 5 and coded using the Medical Dictionary for 
Regulatory Activities (MedDRA).  The focus of AE summaries will be on Treatment 
Emergent Adverse Events, those with initial onset or increasing in severity after the first dose 
of study treatment.  The number and percentage of subjects who experienced any AE, serious 
AE (SAE), treatment-related AE, and treatment-related SAE will be summarized according to 
worst toxicity grades.  The summaries will present AEs both on the entire study period and by 
cycle (Cycle 1 and Cycles beyond 1). 
The Sponsor-investigator will report all unanticipated problems involving risks to human 
subjects or others to the IRB of record and to the Stanford SCI Data and Safety Monitoring 
Committee (DSMC).  
Laboratory Test Abnormalities 
The number and percentage of subjects who experienced laboratory test abnormalities will be 
summarized according to worst toxicity grade observed for each laboratory assay.  The 
analyses will summarize laboratory tests both on the entire study period and by cycle (Cycle 1 
and Cycles beyond 1).  Shift tables will be provided to examine the distribution of laboratory 
toxicities. 
For laboratory tests without CTCAE grade definitions, results will be categorized as normal, 
abnormal, or not done. 


 
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Appendix 1.  Determination of Efficacy – Solid Tumors  
CATEGORIZING LESIONS AT BASELINE  
Measurable Lesions 
 Lesions that can be accurately measured in at least one dimension. 
 Lesions with longest diameter twice the slice thickness and at least 10 mm or greater when 
assessed by CT or MRI (slice thickness 5 to 8 mm). 
 Lesions with longest diameter at least 20 mm when assessed by chest X-ray. 
 Superficial lesions with longest diameter 10 mm or greater when assessed by caliper. 
 Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT. 
NOTE:  The shortest axis is used as the diameter for malignant lymph nodes, longest 
axis for all other measurable lesions. 
Non-measurable disease 
Non-measurable disease includes lesions too small to be considered measurable (including 
nodes with short axis between 10 and 14.9 mm) and truly non-measurable disease such as 
pleural or pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, 
lymphangitic involvement of skin or lung, clinical lesions that cannot be accurately measured 
with calipers, abdominal masses identified by physical exam that are not measurable by 
reproducible imaging techniques. 
 Bone disease: Bone disease is non-measurable with the exception of soft tissue 
components that can be evaluated by CT or MRI and meet the definition of measurability 
at baseline. 
 Previous local treatment: A previously irradiated lesion (or lesion subjected to other local 
treatment) is non-measurable unless it has progressed since completion of treatment. 
Normal sites 
 Cystic lesions: Simple cysts should not be considered as malignant lesions and should not 
be recorded either as target or non-target disease.  Cystic lesions thought to represent 
cystic metastases can be measurable lesions, if they meet the specific definition above.  
If non-cystic lesions are also present, these are preferred as target lesions. 
 Normal nodes: Nodes with short axis < 10 mm are considered normal and should not be 
recorded or followed either as measurable or non-measurable disease. 
RECORDING TUMOR ASSESSMENTS 
All sites of disease must be assessed at baseline.  Baseline assessments should be done as 
close as possible prior to study start.  For an adequate baseline assessment, all required scans 
must be done within 28 days prior to treatment and all disease must be documented 
appropriately.  If baseline assessment is inadequate, subsequent statuses generally should be 
indeterminate. 
Target lesions 
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at baseline.  Target 


 
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lesions should be selected on the basis of size (longest lesions) and suitability for accurate 
repeated measurements.  Record the longest diameter for each lesion, except in the case of 
pathological lymph nodes for which the short axis should be recorded.  The sum of the 
diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions at 
baseline will be the basis for comparison to assessments performed on study. 
 If two target lesions coalesce the measurement of the coalesced mass is used.  If a large 
target lesion splits, the sum of the parts is used. 
 Measurements for target lesions that become small should continue to be recorded.  If a 
target lesion becomes too small to measure, 0 mm should be recorded if the lesion is 
considered to have disappeared;; otherwise a default value of 5 mm should be recorded. 
NOTE: When nodal lesions decrease to < 10 mm (normal), the actual measurement 
should still be recorded. 
Non-target disease 
All non-measurable disease is non-target.  All measurable lesions not identified as target 
lesions are also included as non-target disease.  Measurements are not required but rather 
assessments will be expressed as ABSENT, INDETERMINATE, PRESENT/NOT 
INCREASED, INCREASED.  Multiple non-target lesions in one organ may be recorded as a 
single item on the case report form (eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple 
liver metastases’). 
OBJECTIVE RESPONSE STATUS AT EACH EVALUATION. 
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast and timing of scanning.  If a change needs to be made the case must 
be discussed with the radiologist to determine if substitution is possible.  If not, subsequent 
objective statuses are indeterminate. 
Target disease 
 Complete Response (CR): Complete disappearance of all target lesions with the exception 
of nodal disease.  All target nodes must decrease to normal size (short axis < 10 mm).  All 
target lesions must be assessed. 
 Partial Response (PR): Greater than or equal to 30% decrease under baseline of the sum of 
diameters of all target measurable lesions.  The short diameter is used in the sum for target 
nodes, while the longest diameter is used in the sum for all other target lesions.  All target 
lesions must be assessed. 
 Stable: Does not qualify for CR, PR or Progression.  All target lesions must be assessed.  
Stable can follow PR only in the rare case that the sum increases by less than 20% from 
the nadir, but enough that a previously documented 30% decrease no longer holds. 
 Objective Progression (PD): 20% increase in the sum of diameters of target measurable 
lesions above the smallest sum observed (over baseline if no decrease in the sum is 
observed during therapy), with a minimum absolute increase of 5 mm. 
 Indeterminate.  Progression has not been documented; and 
o One or more target measurable lesions have not been assessed; or 
o Assessment methods used were inconsistent with those used at baseline; or 


 
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o One or more target lesions cannot be measured accurately (eg, poorly visible unless 
due to being too small to measure); or 
o One or more target lesions were excised or irradiated and have not reappeared or 
increased. 
Non-target disease 
 CR: Disappearance of all non-target lesions and normalization of tumor marker levels.  
All lymph nodes must be ‘normal’ in size (< 10 mm short axis). 
 Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level above 
the normal limits. 
 PD: Unequivocal progression of pre-existing lesions.  Generally the overall tumor burden 
must increase sufficiently to merit discontinuation of therapy.  In the presence of SD or 
PR in target disease, progression due to unequivocal increase in non-target disease should 
be rare. 
 Indeterminate: Progression has not been determined and one or more non-target sites were 
not assessed or assessment methods were inconsistent with those used at baseline. 
New Lesions 
The appearance of any new unequivocal malignant lesion indicates PD.  If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the etiology.  If 
repeat assessments confirm the lesion, then progression should be recorded on the date of the 
initial assessment.  A lesion identified in an area not previously scanned will be considered a 
new lesion. 
Supplemental Investigations 
If CR determination depends on a residual lesion that decreased in size but did not disappear 
completely, it is recommended the residual lesion be investigated with biopsy or fine needle 
aspirate.  If no disease is identified, objective status is CR. 
If progression determination depends on a lesion with an increase possibly due to necrosis, the 
lesion may be investigated with biopsy or fine needle aspirate to clarify status. 
Subjective progression 
Subjects requiring discontinuation of treatment without objective evidence of disease 
progression should not be reported as PD on tumor assessment CRFs.  This should be 
indicated on the end of treatment CRF as off treatment due to Global Deterioration of Health 
Status.  Every effort should be made to document objective progression even after 
discontinuation of treatment. 


 
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Objective Response Status at each Evaluation 
Target Lesions 
Non-target Lesions 
New Lesions 
Objective status 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
 
No 
 
 
Indeterminate or Missing 
 
PR 
PR 
Non-CR/Non-PD, Indeterminate, or Missing 
No 
PR 
SD 
Non-CR/Non-PD, Indeterminate, or Missing 
No 
Stable 
Indeterminate or 
Missing 
Non-PD 
No 
Indeterminate 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Adapted from: Eisenhauer EA, Therasse P, Bogaerts J, et al.  “New response evaluation criteria in solid 
tumours:  revised RECIST guideline (version 1.1).”  Eur J Cancer.  Jan 2009;45(2):228-247. 


 
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Appendix 2:  ECOG Performance Status 
Score 
Definition 
0 
Fully active, able to carry on all pre-disease activities without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, eg, light house work or office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities.  Up 
and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled.  Cannot carry on any selfcare.  Totally confined to bed or chair 
5 
Dead 
 
From: Oken MM, Creech RH, Tormey DC, et al.  Toxicity and response criteria of the 
Eastern Cooperative Oncology Group.  Am J Clin Oncol.  1982;5:649–655. 
 
090177e1869e9927\ 
 


 
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Appendix 3:  Schedule of Activities  
Protocol Activity  
(Cycle Day relative to utomilumab dosing) 
Screening 
On Treatment (1 Cycle = 21 days) 
Post-Treatment 
(Within 
28 days of 
Cycle 1, 
Day 0) 
Cycle 1 
Cycle 2 
Cycles ≥ 3 End of Treatment / 
withdrawal 
(within 28 days 
from final dose) 28 Follow-Up 30 
Day 0 
(± 2 
business 
days) 
Day 1 
(± 2 
business 
days) 
Day 8 
(± 2 
business 
days) 
Day 15 
(± 2 
business 
days) 
Day 1 
(± 2 
business 
days) 
 
 
Day 1 
(± 2  
business  
days) 
Baseline documentation 
Informed Consent 1 
X 
 
 
 
 
 
 
 
 
 
 
Medical/Tumor History 2 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examination (within 24 hours prior 
to start of each cycle) 3 
X 
X 
 
 
 
X 
 
 
X 
X 
(X) 
ECOG Performance Status (± 3 days) 4 
X 
X 
 
 
 
X 
 
 
X 
X 
(X) 
Safety Labs/ Measurements 
Vital signs (BP and pulse, within 24 hours 
prior to start of each cycle) 5 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
(X) 
12 lead ECG (± 3 days) 6 
X 
 
X 
 
 
X 
 
 
 
X 
(X) 
Hematology (CBC, differential, platelets) 7 
X 
X 
 
X 
X 
X 
 
 
X 
X 
(X) 
Coagulation (PT/INR and PTT) 8 
X 
X 
 
 
 
X 
 
 
X 
X 
(X) 
Blood Chemistry 9 
X 
X 
 
X 
X 
X 
 
 
X 
X 
(X) 
Urinalysis 10 
X 
 
 
 
 
 
 
 
 
X 
(X) 
Hepatitis B and C testing 11 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 12 
X 
X 
 
 
 
X 
 
 
X 
X 
(X) 
Endocrine function 13 
X 
 
 
 
 
 
 
 
 
 
 
LVEF assessment 14 
X 
 
 
 
 
 
 
 
Cycle 5 Day 1, 
then every 
4th cycle 
(± 7 days) 
X 
 
Registration 1  
≤ 7 days 
before 
Cycle 1, Day 0 
 
 
 
 
 
 
 
 
 
 
Treatment 
Administration of utomilumab 15 
 
 
X 
 
 
X 
 
 
X 
 
 
Administration of 
ado-trastuzumab emtansine or trastuzumab 16 
 
X 
 
 
 
X 
 
 
X 
 
 


 
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Protocol Activity  
(Cycle Day relative to utomilumab dosing) 
Screening 
On Treatment (1 Cycle = 21 days) 
Post-Treatment 
(Within 
28 days of 
Cycle 1, 
Day 0) 
Cycle 1 
Cycle 2 
Cycles ≥ 3 End of Treatment / 
withdrawal 
(within 28 days 
from final dose) 28 Follow-Up 30 
Day 0 
(± 2 
business 
days) 
Day 1 
(± 2 
business 
days) 
Day 8 
(± 2 
business 
days) 
Day 15 
(± 2 
business 
days) 
Day 1 
(± 2 
business 
days) 
 
 
Day 1 
(± 2  
business  
days) 
Tumor Assessment  
CT scan with contrast (chest, abdomen, + 
pelvis) plus radionucleide bone scan or 
CT/PET with contrast.  CNS imaging by CT 
or MRI if CNS metastasis present 17 
X 
 
 
 
 
 
 
 
Cycle 4 Day 1, 
then every 
3rd cycle 
(± 7 days) 
while  
on treatment 
X 
 
Pharmacokinetic, Pharmacodynamic Assessments 
Blood for utomilumab PK 6, 18 
 
 
X 
 
 
X 
 
 
X 
X 
 
Blood for ado-trastuzumab 
emtansine / trastuzumab PK 6, 19 
 
X 
 
 
 
X 
 
 
X 
X 
 
Blood for biomarkers linked with 
immunomodulation / cytokine release 20 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
Pharmacodynamic assessment of lymphocyte 
subpopulation 21 
X 
 
 
 
 
X 
 
 
 
X 
 
T cell receptor assessment 22 
X 
 
 
 
 
X 
 
 
 
X 
 
Blood for utomilumab immunogenicity 
(ADA) testing 23 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Blood for ado-trastuzumab 
emtansine / trastuzumab immunogenicity 
(ADA) testing 24 
 
X 
 
 
 
X 
 
 
X 
X 
X 
Blood for exploratory biomarkers 25  
X 
 
 
 
 
X 
 
 
 
X 
 
Optional tumor biopsy for biomarker 
assessment 26 
X 
 
 
 
 
 
 
 
X (Cycle 4) 
 
 
Other Clinical Assessment 
Adverse event 27 
X 
Monitor and record at every study visit 
X 
X 
Concomitant medication 28 
X 
Monitor and record at every study visit 
X 
 
 
Note:  1 cycle = 21 days ± 2 business days 


 
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1.  Informed Consent:  Must be obtained prior to undergoing any study specific procedure and may occur prior to the 28-day screening period.  Registration will considered to be signed informed 
consent with triple-signed eligibility checklist, with the final signature being the Stanford Principal Investigator or his designee.  
2.  Medical History/Tumor History:  To be collected within 28 days prior to registration (registration is defined as signed informed consent plus PI-signed confirmation of all eligibility criteria).  
Includes history of other diseases (active or resolved) and concomitant illnesses.  Include oncology history; information on prior regimens (including dosing and duration of administration, 
description of best response observed, recurrence date), surgery and radiation therapy. 
3.  Physical Examination:  Includes an examination of major body systems.  Weight for the purposes of dose calculation will be recorded at screening and within 7 days pre-dose Day 1 of each 
cycle.  Weight may not be collected at End of Treatment.  Height will be measured at baseline. 
4.  ECOG PS:  ECOG performance scale is available as Appendix 6 in the full protocol. 
5.  Blood pressure (BP) and pulse rate to be recorded in supine or sitting position. 
6.  12-lead ECG and pharmacokinetics:  At each time point, a 12-lead ECG will be performed to determine QTc.  ECGs and blood sample draws for PK and other research assessments should be 
done at 2 separate time points prior and post-infusion when applicable, with no preference to the order of performance.  ECGs will be performed at screening, on Day 1 of Cycles 1 and 2 before and 
at the end of utomilumab infusion.  If the QTc interval is prolonged (> 500 msec), then the ECGs should be reevaluated by a qualified person at the center for confirmation.  Additional ECGs may be 
performed as clinically indicated. 
7.  Hematology:  No need to repeat on C1D1 if baseline assessment performed within 7 days prior to that date.  On treatment, to be performed prior to dosing with study medications unless 
otherwise indicated.  If during the first cycle of treatment a Grade 4 hematologic event is evident, the hematology assessment should be repeated at least on or after 7 days later to assess for events 
qualifying as DLT. 
8.  Coagulation:  No need to repeat on C1D1 if baseline assessment performed within 7 days prior to that date.  On treatment, to be performed prior to dosing with study medications unless 
otherwise indicated. 
9.  Blood Chemistry:  Blood chemistry collection as shown for first cycle; thereafter, blood chemistry collection required only within 72 hours prior to beginning of each cycle. 
10.  Urinalysis:  Conducted for all subjects at screening.  During the treatment period to be performed only when clinically indicated.  If protein ≥ 2+ by semiquantitative method (eg, urine dipstick), 
protein will be quantified by 24-hour urine collection.  Urine reflex microscopy is recommended whenever urine multitest dipstick is positive for blood or protein. 
11.  Hepatitis B and C Testing:  Conduct tests for hepatitis B surface antigen, core antibody, and anti-hepatitis C.  Other standard tests may be conducted to confirm an active hepatitis infection. 
12.  Pregnancy Test:  For female subjects of childbearing potential, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL, and assayed in a certified laboratory, will be performed 
on 2 separate occasions prior to starting study treatment:  once at the start of screening and once at the baseline visit (except if screening and baseline are within 2 days of each other).  Negative 
results for the baseline pregnancy must be obtained and documented before ado-trastuzumab emtansine administration.  Following a negative pregnancy result at screening, appropriate contraception 
must be commenced.  Pregnancy tests to be routinely repeated at every cycle (eg, on Day 1) during the active treatment period.  Additional pregnancy test to be repeated whenever one menstrual 
cycle is missed or when potential pregnancy is otherwise suspected. 
13.  Endocrine Function:  Assessed by medical history, physical examination, and routine laboratory parameters (eg, blood chemistries) for endocrine function (including but not limited to TSH, 
ACTH, and cortisol levels), and as medically appropriate may include assessment for hypopituitarism and hypoadrenalism.  Conducted for all subjects at screening/baseline, and when clinically 
indicated during the treatment period. 
14.  LVEF Assessment:  Performed at screening; at Cycle 5 Day 1 (± 7 days);   every 4 cycles (± 7 days) thereafter;  and at end of treatment. 
15.  Utomilumab Administration:  Treatment will be administered in a 3-week cycle (ie, 21-day cycle).  Utomilumab will be administered as a 1-hour intravenous infusion (± 15 minutes) on Day 1 
of each cycle.  When both utomilumab and ado-trastuzumab emtansine/trastuzumab are administered, ado-trastuzumab emtansine/trastuzumab will be administered first, followed within 30 minutes 
(± 15 min) by utomilumab infusion. 
16.  Ado-trastuzumab emtansine or trastuzumab Administration:  Treatment will be administered in a 3-week cycle (ie, 21-day cycle), by intravenous infusion.  The first infusion of 
ado-trastuzumab emtansine or trastuzumab on-study will be over 90 minutes (± 30 minutes) on Cycle 1 Day 0.  Subsequent infusions will be administered over 30 ± 15 minutes as tolerated. 
17.  Tumor assessment:  Assessment of response will be made using RECIST v1.1.  Antitumor activity will be assessed through radiological tumor assessments conducted a baseline, on treatment 
every 9 weeks and whenever disease progression is suspected (eg, symptomatic deterioration).  To be repeated at End of Treatment/Withdrawal only if not done in the previous 9 weeks.  
Confirmation of response (CR/PR) should be done at least 4 weeks after the initial response.  The allowable time window for disease assessments is ± 7 business days, on treatment, starting from 
C1D1.  Timing should follow calendar days and should not be adjusted for delays in cycle starts.  Tumor assessments performed after the screening period should consist of 1) CT and/or MRI of the 
chest/abdomen/pelvis;  2) bone scan or PET scan if bone metastases identified during the screening period are clinically indicated by the treating physician;  and 3) CNS imaging clinically indicated 
by the treating physician. 


 
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18.  Blood for utomilumab pharmacokinetics:  Blood samples (tube type and quantity per lab manual) will be collected as follow: Cycles 1 to 3 on Day 1 at pre-dose and at the end of utomilumab 
infusion; From Cycle 4 onwards, it will be collected on Day 1 at pre-dose of every 3 cycles (eg, Cycle 4;  Cycle 7;  Cycle 10;  etc).  For subjects discontinuing from the study, a PK sample should be 
collected at the End of Treatment assessment.  
19.  Blood for ado-trastuzumab emtansine or trastuzumab pharmacokinetics:  Blood samples (tube type and quantity per lab manual) will be collected as follows: Cycle 1 on Day 0 at pre-dose 
and a the end of ado-trastuzumab emtansine or trastuzumab infusion; Cycle 2 to 3 on Day 1 at pre-dose and at the end of ado-trastuzumab emtansine or trastuzumab infusion.  From Cycle 4 onwards, 
it will be collected on Day 1 at pre-dose of every 3 cycles (eg, Cycle 4;  Cycle 7;  Cycle 10;  etc).  For subjects discontinuing from the study, a PK sample should be collected at the End of Treatment 
assessment.  
20.  Blood for Immunomodulation/Cytokine Release Biomarkers:  Blood samples (tube type and quantity per lab manual) will be collected as follows:  at Screening, Cycles 1 on Day 0 at 
pre-dose and at the end of infusion of ado-trastuzumab emtansine or trastuzumab;  Cycles 1 on Day 1 at pre-dose and at the end of infusion of utomilumab;  on Day 8 and Day 15 of Cycle 1; on 
Day 1 of Cycle 2 at pre-dose; at end of treatment.  
21.  Blood for Pharmacodynamic Assessment of Lymphocyte Subpopulation:  Blood samples (tube type and quantity per lab manual) for the isolation and analysis of lymphocytes subpopulation 
will be collected at screening, on Cycle 2 Day 1 at pre-dose, and at end of treatment.  
22.  Blood for T cell Receptor Assessment:  Blood samples (tube type and quantity per lab manual) for the isolation and analysis of T-cell receptors will be collected at screening, on Cycle 2 Day 1 
at pre-dose, and at end of treatment.   
23.  Blood for utomilumab Immunogenicity Testing:  Blood samples (tube type and quantity per lab manual) for utomilumab immunogenicity testing will be collected on Cycles 1 to 3 on Day 1 at 
pre-dose.  From Cycle 4 onwards, blood samples will be collected on Day 1 at pre-dose every 4 cycles (eg, Cycle 8;  Cycle 12;  Cycle 16;  etc).  For subjects discontinuing study drug treatment, 
immunogenicity samples should be collected at the End of Treatment and at Follow-Up.  If ADAs are detected, additional samples may be collected approximately every 9 weeks (coinciding with 
disease assessment visit) until ADA levels return to baseline.  
24.  Blood for ado-trastuzumab emtansine/trastuzumab Immunogenicity Testing:  Blood samples (tube type and quantity per lab manual) for ado-trastuzumab emtansine or trastuzumab 
immunogenicity testing will be collected on Cycles 1 on Day 0 at pre-dose and on Cycle 2 and 3 on Day 1 at pre-dose.  From Cycle 4 onwards, blood samples will be collected on Day 1 at pre-dose 
every 4 cycles (eg, Cycle 8;  Cycle 12;  Cycle 16;  etc).  For subjects discontinuing study drug treatment, immunogenicity samples should be collected at the End of Treatment and at Follow Up.  If 
ADAs are detected, additional samples may be collected approximately every 9 weeks (coinciding with disease assessment visit) until ADA levels return to baseline.  
25.  Blood for Exploratory Biomarkers:  Blood samples (tube type and quantity per lab manual) will be collected at Screening, on Cycle 2 Day 1 at pre-dose, and at end of treatment.  
26.  Tumor Biopsy for Biomarker Assessment:  See Appendix 4.  A recent tumor biopsy is requested be provided at enrollment.  An archival biopsy may be acceptable per eligibility criteria (see 
inclusion criteria).  Tissue blocks are preferred, but if not available at least 20 unstained slides are suggested.  For eligibility, if no unstained slides remain, stained pathology slides should be 
reviewed at the treating institution.  A tumor biopsy at Day 1, Cycle 4 (± 14 days) is requested unless clinically not feasible.  
27.  Adverse Event (AE) Assessments:  Adverse events should be documented and recorded at each scheduled or unscheduled visit, including at end-of-treatment and during follow-up, using 
NCI CTCAE v5.  Subjects must be followed for AEs for 28 days after the last treatment administration or until all drug-related toxicities have resolved, whichever is later; or earlier than 28 days 
should the subject commence another anticancer therapy in the meantime.  For serious adverse events (SAEs), the active reporting period to Pfizer or its designated representative begins from the 
time that the subject provides informed consent, which is obtained prior to the subject’s participation in the study, ie, prior to undergoing any study-related procedure and/or receiving investigational 
product, through and including 60 calendar days after the last administration of the investigational products and before initiation of a new anti-cancer treatment.  The prolonged follow up is due to 
the pharmacokinetic properties of the investigational product utomilumab.  SAEs experienced by a subject after the active reporting period has ended should be reported to the Sponsor if the 
Investigator becomes aware of them; at a minimum, all SAEs that the Investigator believes have at least a reasonable possibility of being related to study drug are to be reported to the Sponsor.  
AEs (serious and non-serious) should be recorded on the Case Report Form (CRF) from the time the subject has taken at least one dose of study treatment through last subject visit (Day 28 after last 
dose).  If a subject begins a new anticancer therapy, the AE reporting period for non-serious AEs ends at the time the new treatment is started.  Pregnancy or breast feeding that occur during the trial, 
within 28 days after the cessation of utomilumab if the subject begins a new anticancer therapy, whichever is earlier, should be reported as SAE.  
28.  Concomitant Medications:  Concomitant medications will be recorded from 28 days prior to the start of study treatment and up to 28 days after the last dose of study treatment.  Concomitant 
medications will be collected at each scheduled or unscheduled visit, including at end-of-treatment.  All concomitant medications should be recorded in the CRF including supportive care drugs (eg, 
anti-emetic treatment and prophylaxis), and the drugs used to treat adverse events or chronic diseases, and non-drug supportive interventions (eg, transfusions). 
29.  End of Treatment:  To be performed 28 days (± 7 days) after the last dose of study drug.  Obtain these assessments if not completed during the previous week on study, (during the previous 
9 weeks on study, for tumor assessments).  
30.  Follow-Up:  Subjects should be evaluated, including for adverse events, up to 60 days after last dose of study treatment.  Subjects continuing to experience toxicity following discontinuation of 
study treatment will continue to be followed including for adverse events, at least every 3 weeks until resolution or determination, in the clinical judgment of the Investigator, that no further 
improvement is expected.  Adverse events will not be collected after resolution of treatment-related toxicities or 60 days after last dose of study treatment, whichever is later.  Subjects whose disease 
has not progressed at the end of treatment will enter into disease follow-up.  During this follow up period, subjects will have disease assessments performed every 9 weeks (± 7 days).  Once subjects 


 
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have exhibited disease progression or began a new anticancer therapy, or 6-month follow-up from the date of the last dose of the study drug, whichever occurs first, they will be withdrawn from the 
study.   


 
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Appendix 4:  Tumor Biopsy Recommendations 
Optional tumor biopsies for subjects with accessible tumors are strongly encouraged.  Suggested 
time points are as follows:  Baseline pre-treatment, and on Cycle 4 Day 1 ± 14 days.  These are 
suggested time points; but tissue sample collection may be obtained at any time point as feasible 
(eg, during drainage of pleural fluid for symptom relief, etc). 
Tissue collection kits will be provided: 
1.  Tumor specimens will be obtained from accessible tumor sites as follows: 
a.  Fine Needle Aspiration (FNA) -- to be used only if core biopsy is not allowed or if not 
feasible.  The needle aspirate biopsies will be apportioned by pathology into multiple 
types of media for assessment.  Portions of specimen must be prioritized in the following 
order at the discretion of the pathologist involved in the case/responsible for the trial: 
i. Smears for histology and diagnosis 
ii.  Tissue frozen at -80ºC for RNA/DNA isolation/analysis 
iii.  Fresh frozen tissue for optimum cutting temperature (OCT) compound. 
b.  Core biopsy: 2 to 3 large bore (3 mm) needle biopsies of accessible, involved sites will be 
made at the time points suggested above.  The needle aspirate biopsies will be 
apportioned by pathology into multiple types of media for assessment.  Portions of 
specimen must be prioritized in the following order at the discretion of the pathologist 
reviewing the case /responsible for the trial: 
i. Portion of core submitted for formalin-fixed, paraffin-embedded (FFPE) processing to be 
used for histology and diagnosis, for FFPE compatible immunohistochemistry and in situ 
hybridization 
ii.  Tissue frozen at -80ºC for RNA/DNA isolation/analysis 
iii. Fresh frozen tissue embedded in optimum cutting temperature (OCT) compound for 
immunohistochemistry and in situ hybridization that requires fresh frozen tissue, and 
for Western blot analysis. 
iv. Viably frozen tumor cells, dissociated for other cellular experimentation and for flow 
analysis to determine percentage of tumor cells vs infiltrating lymphocytes, etc. 
c.  Excisional biopsy: Tissue will be taken and apportioned by pathology into multiple types 
of media for assessment.  Portions of specimen must be prioritized in the following order 
and will be at the discretion of the pathologist reviewing the case/responsible for the trial: 
i. Portion of the specimen will be submitted for FFPE processing to be used for 
histology and diagnosis, determination of treatment effect (degree of necrosis 
compared to original diagnostic material), determination of local variations (periphery 
of tumor vs center) for FFPE compatible immunohistochemistry and in situ 
hybridization. 
ii Tissue frozen at -80ºC for RNA/DNA isolation/analysis 
iii.  Fresh frozen tissue embedded in optimum cutting temperature (OCT) compound for 
immunohistochemistry and in situ hybridization that requires fresh frozen tissue, and 
for Western blot analysis. 
iv. Viably frozen tumor cells, dissociated for other cellular experimentation and for flow 
analysis to determine percentage of tumor cells vs infiltrating lymphocytes, etc. 


 
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v.  Fresh viable (non-frozen) tissue for consideration for implantation into mice to 
develop xenograft models and extend tumors for further experimentation. 
d.  Paracentesis/thoracocentesis/lumbar puncture:  Cells in the fluid obtained from 
paracentesis/thoracentesis/lumbar puncture will be spun down and cell count taken.  
Tissue will be taken and apportioned by pathology into multiple types of media for 
assessment.  Portions of specimen must be prioritized in the following order and will be 
at the discretion of the pathologist reviewing the case/responsible for the trial: 
i. Smear for histology and diagnosis, eg, determination of percentage of tumor 
cells vs inflammatory cells. 
ii.  Fresh cells for flow analysis to determine percentage of tumor cells vs infiltrating 
lymphocytes, vs mesothelial cells, etc. 
iii.  Tissue for RNA/DNA analysis 
iv.  Fresh frozen tissue embedded in optimum cutting temperature (OCT) compound for 
immunohistochemistry and in situ hybridization that requires fresh frozen tissue, and 
for Western blot analysis. 
v.  Viably frozen tissue for other cellular experimentation 
vi.  Remainder of the cell pellet will be submitted for FFPE for FFPE compatible 
immunohistochemistry and in situ hybridization. 


 
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Appendix 5: Correlative / Special Studies – Biomarkers  
• 
Serum and intratumoral biomarkers linked to immunomodulation and cytokine release such 
as:  TNFα;  IL-6;  IFNγ;  CXCL9;  CXCL10;  IL10;  IL-8;  IL-4;  IL-2;  IL-1b;  IL-12p70  
• 
Exploratory PD biomarkers expressed by PBMC and intratumoral lymphocytes, such as 
Ki67, soluble CD137, and markers of T and NK cell phenotype (such as CD3;  CD4;  CD8;  
CD25;  HLA-DR;  CCR7;  ICOS;  Eomesodermin;  CD45RA;  CD45RO;  CD16;  CD56;  
CD25;  CXCR6;  TNFSF4;  TNFSF7;  ITGA2;  ITGB7;  VCAM1) and quantitation of T-cell 
receptor sequences; 
• 
Tumor biopsy for analysis of exploratory mechanistic biomarkers such as IHC assessment of 
tumor-infiltrating lymphocytes and quantitation of T-cell receptor sequences; 
• 
(Optional blood and intratumoral sample) Pharmacogenomic (RNA) analysis of subject 
PBMC to explore expression of genes that would influence subject response to utomilumab 
and TDM-1 or trastuzumab, such as EOMES;  CDKN2D;  TIMP1;  FCGR2B;  IL1RN;  
SOCS3;  CXCL9;  CXCL10;  IL1B;  IFI16;  CCR5;  FASLG;  CXCR3;  IFNG;  ICOS;  
CD40LG;  IL2RA;  CD80;  CCL5;  FOXP3;  CDC25A,GZMA;  IL23A;  SOCS1;  IL10; 
• 
(Optional blood and intratumoral sample) Pharmacogenetic (DNA) analysis of subject 
PBMC to explore polymorphisms in genes such as FCGR2A and FCGR3A that could affect 
response to utomilumab and TDM-1 or trastuzumab 


 
IRB-37299 
Page 86 of 87 
21 September 2020 
Appendix 6.  List of Abbreviations: 
4-1BB 
CD137, a member of the tumor necrosis factor (TNF) receptor family.  
Alternative names are tumor necrosis factor receptor superfamily member 9 
(TNFRSF9) and induced by lymphocyte activation (ILA). 
AC 
Adriamycin plus cyclophosphamide chemotherapy 
ADA 
Anti-drug antibody 
ADCC 
Antibody dependent cellular cytotoxicity 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of variance 
APC 
Antigen-presenting cell 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase 
ANC 
Absolute neutrophil count 
CFR 
Code of Federal Regulations 
CL 
Clearance 
CNS 
Central nervous system 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common terminology criteria for adverse events 
DC 
Dendritic cell 
DLT 
Dose-limiting toxicity 
DR 
Duration of response 
DSMC 
Data safety and monitoring committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
FFPE 
Formalin-fixed paraffin embedded 
FIH 
First-in-human 
FISH 
Fluorescence in situ hybridization 
FL 
Follicular lymphoma 
FNA 
Fine needle aspirate 
GCP 
Good clinical practice 
HER2 
Human epidermal growth factor receptor 2 
IHC 
Immunohistochemistry 
ILD 
Interstitial lung disease 
IRB 
Institutional review board 
IRR 
Infusion related reaction 
IV 
Intravenous 
LNG-IUS  
Levonorgestrel-releasing intrauterine system 
LVEF 
Left ventricular ejection fraction 
mAb 
Monoclonal antibody 
MAP 
Mitogen activated protein 
MCC 
Merkel Cell Carcinoma 


 
IRB-37299 
Page 87 of 87 
21 September 2020 
MCL 
Mantle cell lymphoma 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
MUGA 
Multi-gated acquisition 
NCI 
National cancer institute 
NHL 
Non-Hodgkin’s lymphoma 
OCT 
Optimum cutting temperature 
PBMC 
Peripheral blood mononuclear cells 
PD 
Progressive disease 
PET 
Positron emission tomography 
PF-05082566 Utomilumab, a humanized anti-CD137 monoclonal antibody  
PFS 
Progression-free survival 
PK 
Pharmacokinetics 
PR 
Partial response 
RECIST 
Response evaluation criteria in solid tumors 
RP2D 
Recommended phase 2 dose 
SAE 
Serious adverse event 
SRC 
Scientific review committee 
TBI 
Total body irradiation 
T-DM1 
Ado-trastuzumab emtansine, a antibody-drug conjugate of trastuzumab  
     and maytansine 1 
TNF 
Tumor necrosis factor 
TRAF 
Tumor necrosis factor receptor-associated factor 
TTR 
Time-to-treatment response 
Vc 
Volume of distribution 
 
 

ICF_001.pdf: 
 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: George Sledge, MD   
Protocol Title:   
A Phase 1B Dose escalation Trial of Human Anti-4-1BB Agonistic 
Antibody utomilumab in Combination with Ado-trastuzumab Emtansine or 
Trastuzumab in Patients with Her2-positive Advanced Breast Cancer 
 
 
 
 
 
 
 
Sledge / IRB 37299 ICF 6 October 2020  
Page 1 of 28 
IRB Use Only 
Approval Date:   October 13, 2020 
Expiration Date: October 13, 2021 
Participant ID: 
Are you participating in any other research studies? _____ Yes _____No 
PURPOSE OF RESEARCH 
You are being asked to take part in this research study because you have advanced cancer that 
is no longer responsive to standard anti-cancer therapies of proven effectiveness and for which 
new therapies need to be developed.  
There are two parts to this study, Cohort 1 and Cohort 2.  Cohort 2 has closed.  Only Cohort 1 is 
active, which will be explained throughout this consent form.  In Cohort 1, the study team hopes 
to learn if utomilumab (also known as PF-05082566), plus ado-trastuzumab emtansine (referred 
to in this document as T-DM1, also known as Kadcyla), is safe at several doses of utomilumab, 
and if there is any beneficial effect of the combination at those doses.   
Utomilumab is a new investigational drug.  An investigational drug is one that is currently 
not approved for sale in this country.  Utomilumab is an antibody, a type of protein, which has 
been shown in animal studies to stimulate the immune system.  Because this is a research 
study, utomilumab will be given to you only during this study and not after the study is over. 
There may be up to about 25 people enrolled into this study.  At this time, participants are only 
enrolling to Cohort 1, utomilumab 100 mg in combination with T-DM1 (3.6 mg/kg).  The study is 
being performed at Stanford University, but other sites may eventually participate. 
VOLUNTARY PARTICIPATION  
Your participation in this study is entirely voluntary.  Your decision not to participate will not have 
any negative effect on you or your medical care.  You can decide to participate now, but 
withdraw your consent later and stop being in the study without any loss of benefits or medical 
care to which you are entitled. 
DURATION OF STUDY INVOLVEMENT  
Your participation will last up to about 24 cycles, including up to 18 months of treatment.  There 
will be a 28-day screening period, up to 24 cycles of treatment (each cycle is about 21 days) of 
treatment and a follow-up period for up to 60 days after the last dose of study drug.  Additional 
treatment after 24 cycles (about 18 months) may be allowed based on the doctor’s judgment.  
Overall, this research study will be conducted over about 3 years.  
PROCEDURES 
The study will begin with a screening visit.  The purpose of the screening visit is to find out if 
you meet all of the requirements to take part in this research study.  The screening visit 
procedures will be made within the 28 days before the first day of study treatment.  A summary 
of the procedures included in the screening visit is included in the assessments listed below.  
By the end of the screening visit, the study doctor will determine if you are eligible to continue 
into the study.  If you will not be able to continue in the study, the study doctor will explain why 
and will discuss with you other treatment options.  


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: George Sledge, MD   
Protocol Title:   
A Phase 1B Dose escalation Trial of Human Anti-4-1BB Agonistic 
Antibody utomilumab in Combination with Ado-trastuzumab Emtansine or 
Trastuzumab in Patients with Her2-positive Advanced Breast Cancer 
 
 
 
 
 
 
 
Sledge / IRB 37299 ICF 6 October 2020  
Page 2 of 28 
IRB Use Only 
Approval Date:   October 13, 2020 
Expiration Date: October 13, 2021 
Participant ID: 
Study Treatment 
In this study, you will receive 100 mg of utomilumab plus T-DM1 3.6 mg/kg.  
Assessments During the Study 
The following tests/procedures will be done during this study: 
 
Informed Consent:  You will be asked to sign this consent form (performed at 
Screening). 
 
Medical and Tumor History:  The study staff will ask you questions about your medical 
history including oncology history, information on prior treatment regimens.  (performed 
at Screening) 
 
Physical Exam:  Includes an exam of major body systems.  Height will be recorded only 
one time at first exam.  Weight will be recorded at Screening, within 7 days before the 
dose on Day 1 of each treatment cycle (performed at Screening; Day 0 of Cycle 1 and 
above; End of Treatment visit; Follow-up visit.) 
 
A measure of your activity level (performed at Screening; Day 0 of Cycle 1 and above; 
End of Treatment visit; Follow-up visit.) 
 
Vital signs including blood pressure and pulse (Performed at Screening; Cycle 1 Days 
0, 1, 8 and 15; Cycle 2 Day 1; Cycle ≥ 3 Day 1;  End of Treatment visit;  Follow-up.) 
 
ECG:  Measures the electrical activity in your heart.  (Performed at Screening;  
Cycle 1 Day 0;  Cycle 2, Day 1;  End of Treatment Visit;  Follow-up.)  
 
Blood tests for hematology and chemistry are considered “safety lab tests” to make sure 
your organs are functioning properly.  (Performed weekly.  Specific visits include 
Screening;  Cycle 1 Days 0, 1, 8 and 15;  Cycles 2 Day 1, 8, 15;  Cycle ≥ 3 and above at 
Day 1;  End of Treatment visit;  and Follow up visit.  About 1 tablespoon (15 mL) will be 
collected each time.   
 
Blood tests for coagulation are to measure your blood’s ability to clot and will also be 
included in the hematology and chemistry blood draws (Screening;  Cycle 1 and above:  
Days 1;  End of Treatment visit;  and Follow-up visit.   
 
Urine Test (Screening, End of Treatment Visit, and Follow Up). 
 
Blood test for Hepatitis B and C will be taken at screening (2 teaspoons). 
 
Pregnancy Test (Performed at Screening;  Cycle 1 above:  Day 1;  End of Treatment 
Visit;  Follow Up and additional whenever one menstrual cycle is missed or when 
potential pregnancy is otherwise suspected). 
 
Blood test for endocrine function.  It will be 1 teaspoon (5 mL).  (Screening.  If your 
doctor believes it is necessary it may be measured again during the study). 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: George Sledge, MD   
Protocol Title:   
A Phase 1B Dose escalation Trial of Human Anti-4-1BB Agonistic 
Antibody utomilumab in Combination with Ado-trastuzumab Emtansine or 
Trastuzumab in Patients with Her2-positive Advanced Breast Cancer 
 
 
 
 
 
 
 
Sledge / IRB 37299 ICF 6 October 2020  
Page 3 of 28 
IRB Use Only 
Approval Date:   October 13, 2020 
Expiration Date: October 13, 2021 
Participant ID: 
 
Left ventricular ejection fraction (LVEF) assessment.  LEVF is a test of heart function, 
and will be performed at screening;  at Cycle 5 Day 1 (± 7 days);  every 4 cycles 
(± 7 days) thereafter;  and at end of treatment.   
 
Utomilumab administration:  Treatment will be administered in a 3-week cycle (ie, 21-day 
cycle).  Utomilumab will be administered as a 1-hour intravenous infusion on Day 1 of 
each cycle.  When both utomilumab and T-DM1 are administered, T-DM1 will be 
administered first, followed within 30 minutes (± 10 minutes) by utomilumab infusion. 
 
T-DM1 administration:  Treatment will be administered in a 3-week cycle (ie, 21-day 
cycle).  The first infusion of T-DM1 on-study will be over 90 minutes (± 30 minutes), on 
Cycle 1 Day 0.  Subsequent infusions at the beginning of each cycle will be administered 
over 30 ± 15 minutes as tolerated. 
 
An MRI or a CT scan is to be done approximately every 9 weeks starting at screening.  
An MRI or CT will be repeated at the end of the study if more than 9 weeks have 
passed since the last evaluation.  MRIs are a series of pictures taken while you lie on a 
narrow bed inside of a large magnet.  CTs or “CAT” scans are a series of X-rays that 
will be passed through your body while you lie inside a machine.   
 
Blood tests to see how fast your body eliminates utomilumab.  Blood samples [about 
½ teaspoon (2 mL) whole blood at each time point] will be collected as follow:  Cycles 
1 to 3 on Day 1 at pre-dose and at the end of utomilumab infusion; From Cycle 4 
onwards, it will be collected on Day 1 at pre-dose of every 3 cycles (eg, Cycle 4;  
Cycle 7;  Cycle 10;  etc).  For patients discontinuing from the study, a blood sample to 
determine the levels of study drug in the blood (pharmacokinetics, PK) should be 
collected at the End of Treatment assessment. 
 
Blood tests to see how fast your body eliminates TDM1.  Blood samples will be collected 
as follows:  Cycle1 on Day 0 at pre-dose and at the end of T-DM1 infusion; Cycle 2 to 3 
on Day 1 at pre-dose and at the end of T-DM1 infusion.  From Cycle 4 onwards, it will be 
collected on Day 1 at pre-dose of every 3 cycles (eg, Cycle 4;  Cycle 7;  Cycle 10;  etc).  
For patients discontinuing from the study, a PK sample should be collected at the End of 
Treatment assessment. 
 
Blood tests to assess the level of immune activation within your body at screening, 
cycles 1 on Day 0, at pre-dose and at the end of infusion of T-DM1, Cycles 1 on Day 1 
at pre-dose and at the end of infusion of utomilumab, on Day 8 and Day 15 of Cycle 1, 
on Day 1 of Cycle 2 at pre-dose; at end of treatment.   
 
Blood for Exploratory Biomarkers:  About 2 tablespoons (28 mL) blood will be collected 
at Screening, on Cycles 2 on Day 1 at pre-dose, and at end of treatment. 
 
Blood for Pharmacodynamic Assessment of Lymphocyte Subpopulations:  Blood 
samples [about 1½ teaspoons (7.5 mL) whole blood at each time point] will be collected 
at Screening, on Cycles 2 on Day 1 at pre-dose, and at end of treatment. 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: George Sledge, MD   
Protocol Title:   
A Phase 1B Dose escalation Trial of Human Anti-4-1BB Agonistic 
Antibody utomilumab in Combination with Ado-trastuzumab Emtansine or 
Trastuzumab in Patients with Her2-positive Advanced Breast Cancer 
 
 
 
 
 
 
 
Sledge / IRB 37299 ICF 6 October 2020  
Page 4 of 28 
IRB Use Only 
Approval Date:   October 13, 2020 
Expiration Date: October 13, 2021 
Participant ID: 
 
Blood for utomilumab Immunogenicity Testing:  Blood samples [about ½ teaspoon 
(2 mL) whole blood at each time point] for test to determine if you are making antibodies 
against the study drug utomilumab (“immunogenicity testing”) will be collected on 
Cycles 1 to 3 on Day 1 at pre-dose.  From Cycle 4 onwards, blood samples will be 
collected on Day 1 at pre-dose every 4 cycles (eg, Cycle 8, Cycle 12, Cycle 16, etc.).  
For patients discontinuing study drug treatment, immunogenicity samples should be 
collected at the End of Treatment and at Follow Up.  If anti-drug antibodies (ADAs) are 
detected, additional samples may be collected approximately every 9 weeks (coinciding 
with disease assessment visit) until ADA levels return to baseline. 
 
Blood for T-DM1 Immunogenicity Testing:  Blood samples [about ½ teaspoon (2 mL) 
whole blood at each time point] for T-DM1 immunogenicity testing will be collected on 
Cycles 1 on Day 0 at pre-dose and on Cycle 2 to 3 on Day 1 at pre-dose.  From Cycle 4 
onwards, blood samples will be collected on Day 1 at pre-dose every 4 cycles (eg, 
Cycle 8, Cycle 12, Cycle 16, etc.).  For patients discontinuing study drug treatment, 
immunogenicity samples should be collected at the End of Treatment and at Follow Up.  
If ADAs are detected, additional samples may be collected approximately every 9 weeks 
(coinciding with disease assessment visit) until ADA levels return to baseline. 
 
Optional tumor biopsy for biomarker assessment:  A recent tumor biopsy must be 
provided at enrollment.  An archival biopsy may be acceptable if it is recent and 
no anti-tumor therapy has been administered between collection and enrollment in this 
study.  (See below section on Optional Tumor Biopsy for Research).   
 
Signs and symptoms of adverse side effects:  You will be asked about changes to your 
health and any toxicities you may experience due to the study drugs.  This will be done 
continuously throughout the study. 
 
Review of your medications will be done continuously throughout the study from 
28 days prior to the start of the study treatment and up to 28 days after the last dose of 
the study treatment. 
End of Treatment Assessments 
Within 28 days after the last dose of the study drug you will have a series of assessments 
described in the list above.  This is to assess your health and any toxicities you may be 
experiencing as a result of the study procedures.   
Follow-Up Assessments 
Once your treatment is discontinued, you will enter into a follow-up period.  An MRI or CT scan 
will be done approximately every 9 weeks, until your disease has progressed or you begin any 
anti-cancer therapy.  If you have any toxicities that are continuing at this point, you will continue 
to be followed at least every 4 weeks until resolution or until your doctor decides.  You will then 
be contacted to assess how you are doing.  The follow-up period will last from 60 days to 
6 months from the date of the last dose of the study drug if you do not have disease 
progression or a new anticancer therapy. 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: George Sledge, MD   
Protocol Title:   
A Phase 1B Dose escalation Trial of Human Anti-4-1BB Agonistic 
Antibody utomilumab in Combination with Ado-trastuzumab Emtansine or 
Trastuzumab in Patients with Her2-positive Advanced Breast Cancer 
 
 
 
 
 
 
 
Sledge / IRB 37299 ICF 6 October 2020  
Page 5 of 28 
IRB Use Only 
Approval Date:   October 13, 2020 
Expiration Date: October 13, 2021 
Participant ID: 
Optional Tumor Biopsy for Research  
Research using tissue and blood samples is an important way to try to understand human 
disease.  The investigators want to include your tumor samples in additional research.  There 
are several things you should know before allowing your tissues to be studied.   
Participation in the additional research is voluntary.  You do not have to provide any reason for 
your decision, no matter what that decision is.  You may also continue to participate in the main 
study if you decide not to include your blood and tissue in this research. 
The tumor tissue taken will be used to evaluate DNA, RNA, protein or metabolite (a metabolite 
is produced by the action of proteins or the break-down of food, drugs and naturally occurring 
substances) patterns among patients with cancer.  This can help us understand how different 
patients respond to utomilumab.  One tumor sample be collected at the start of the trial.  
Another tumor sample will be collected at Cycle 3, Day 1 if feasible.   
Your blood will be stored under a unique code number associated with the study and linked to 
your personal identifiers, such as your name or medical record number.  Because the samples 
are linked, you have the right to withdraw consent for the usage of these samples at any time.  
You may withdraw from this study at any time.  The investigators might retain the identified 
samples, eg, as part of your routine clinical care, but not for additional research.  Any samples 
left over will be destroyed at the end of the study. 
Any tissues you have donated which are used in research may result in new products, tests or 
discoveries.  In some instances, these may have potential commercial value and may be 
developed and owned by the Investigators, Stanford University and/or others.  However, donors 
of tissues do not retain any property rights to the materials.  Therefore, you would not share in 
any financial benefits from these products, tests or discoveries. 
Tissue Sampling and Genetic Testing 
As part of the research studies on your tumor samples, the Investigators will do genetic testing.  
Genetic testing is research that studies genes, including gene characteristics and gene versions 
that are transmitted by parents to children.  Your genes can affect how your body responds to a 
medication or how it converts it.   
Genetic research raises certain questions about informing you of any results.  Possible risks of 
knowing results include:  anxiety; other psychological distress; and the possibility of insurance 
and job discrimination.  A possible risk of not knowing includes being unaware of the need for 
treatment.  These risks can change depending on the results of the research and whether there 
is a treatment or cure for a particular disease.   
Sometimes patients have been required to furnish information from genetic testing for health 
insurance, life insurance, and/or a job.  A Federal law, the Genetic Information 
Nondiscrimination Act of 2008 (GINA), generally makes it illegal for health insurance 
companies, group health plans, and employers with 15 or more employees to discriminate 
against you based on your genetic information.  This Federal law does not protect you against 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: George Sledge, MD   
Protocol Title:   
A Phase 1B Dose escalation Trial of Human Anti-4-1BB Agonistic 
Antibody utomilumab in Combination with Ado-trastuzumab Emtansine or 
Trastuzumab in Patients with Her2-positive Advanced Breast Cancer 
 
 
 
 
 
 
 
Sledge / IRB 37299 ICF 6 October 2020  
Page 6 of 28 
IRB Use Only 
Approval Date:   October 13, 2020 
Expiration Date: October 13, 2021 
Participant ID: 
genetic discrimination by companies that sell life insurance, disability insurance, or long-term 
care insurance. 
The results of the genetic testing of your blood sample from this project will be used for research 
purposes only, and you will not be told the results of the tests.  You will not directly benefit from 
your participation in this genetic testing, but you might help scientists understand why people 
respond differently to the study medication or convert it differently.  The study could also help to 
identify the type of person who is most likely to benefit from the study medication or develop 
side effects.  
Please indicate your wish to participate in these optional tumor sample by checking the 
appropriate yes or no box. 
☐    I choose to participate in the optional tumor sample for DNA, RNA, Protein and 
Metabolite Evaluation. 
☐   I choose NOT to participate in the optional tumor sample for DNA, RNA, Protein and 
Metabolite Evaluation. 
PARTICIPANT RESPONSIBILITIES           
As a participant, your responsibilities include:  
 
Follow the instructions of the Protocol Director and study staff. 
 
Keep your study appointments.  If it is necessary to miss an appointment, please contact 
the Protocol Director or research study staff to reschedule as soon as you know you will 
miss the appointment. 
 
Tell the Protocol Director or research study staff about any side effects, doctor visits, or 
hospitalizations that you may have. 
 
Tell the Protocol Director or research staff if you believe you might be pregnant or gotten 
your partner pregnant. 
 
Ask questions as you think of them. 
 
Tell the Protocol Director or research staff if you change your mind about staying in the 
study. 
While participating in this research study, you should not take part in any other research project 
without approval from the Protocol Directors of each study.  This is to protect you from possible 
injury arising from such things as extra blood drawing, extra X-rays, the possible interaction(s) 
of research drugs, or other similar hazards. 
WITHDRAWAL FROM STUDY 
If you first agree to participate and then you change your mind, you are free to withdraw your 
consent and discontinue your participation at any time.  Your decision will not affect your ability 
to receive medical care for your disease and you will not lose any benefits to which you would 
otherwise be entitled.   
If you decide to withdraw your consent to participate in this study, you should notify 
George Sledge, MD at XXX-XXX-XXXX. 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: George Sledge, MD   
Protocol Title:   
A Phase 1B Dose escalation Trial of Human Anti-4-1BB Agonistic 
Antibody utomilumab in Combination with Ado-trastuzumab Emtansine or 
Trastuzumab in Patients with Her2-positive Advanced Breast Cancer 
 
 
 
 
 
 
 
Sledge / IRB 37299 ICF 6 October 2020  
Page 7 of 28 
IRB Use Only 
Approval Date:   October 13, 2020 
Expiration Date: October 13, 2021 
Participant ID: 
The Protocol Director may also withdraw you from the study and the study medication may be 
stopped without your consent for one or more of the following reasons:  
 
Failure to follow the instructions of the Protocol Director and study staff; 
 
The study doctor decides that the study is not in your best interest; 
 
The study is stopped by the study investigator, the institutional review board 
(IRB) (a group of people who review the research to protect your rights), by a 
regulatory agency, or by the drug manufacturer, Pfizer;   
 
You become pregnant, intend to become pregnant or are nursing a child 
during this study; 
 
You need treatment not allowed in the study; 
 
Unanticipated circumstances. 
If you leave the study for any reason, the study doctor may ask you to have tests before you are 
released from the study for your safety.  They are designated as “End of Treatment Visit” above. 
If you withdraw or are removed from the study, biological samples (for example, blood or urine 
samples) that have been collected from you can be withdrawn if they have not yet been 
analyzed or destroyed.  If you want your samples withdrawn, you must tell the study team 
before or at the time you leave the study.   
We will tell you if we learn new information that could change your mind about taking part in this 
research study.  If you want to drop out, you should tell us.  We will make sure you can end the 
study in the safest way.  We will also talk to you about follow-up care, if needed. 
POSSIBLE RISKS, DISCOMFORTS, AND INCONVENIENCES  
Any research has some risks, which may include things that could make you sick, make you feel 
uncomfortable, or hurt you.  You might experience negative effects related to the study drug 
while participating in the study.  All research participants taking part in the study will be watched 
carefully for any negative effects; however, the study team does not know all the effects that the 
study drug may have on you.  The study team may give you medicines to help reduce negative 
effects.  These effects may be mild or serious.  Many side effects go away when treatment is 
stopped, but in some cases, it is possible that the side effects could be serious, long lasting, 
permanent, or may even be life threatening or fatal.  You should discuss these with your study 
doctor. 
The negative events that are the most likely to happen to you if you take part in this study are 
listed below.  The study drugs and procedures in this study may have risks that are not known 
at this time.  You will be told in a timely manner of new information that may affect whether you 
will want to continue to participate in this study.  It is important that you report all symptoms and 
side effects that you experience as soon as they occur, whether or not you think they are 
caused by the study drug.  The phone numbers for the study team are listed in this document. 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: George Sledge, MD   
Protocol Title:   
A Phase 1B Dose escalation Trial of Human Anti-4-1BB Agonistic 
Antibody utomilumab in Combination with Ado-trastuzumab Emtansine or 
Trastuzumab in Patients with Her2-positive Advanced Breast Cancer 
 
 
 
 
 
 
 
Sledge / IRB 37299 ICF 6 October 2020  
Page 8 of 28 
IRB Use Only 
Approval Date:   October 13, 2020 
Expiration Date: October 13, 2021 
Participant ID: 
Potential side effects of utomilumab: 
Utomilumab has been administered as a single agent or in combination to over 390 participants 
with advanced cancer at dose levels between 0.006 and 10.0 mg/kg.  Frequent adverse events, 
regardless of relationship to treatment, that occurred in people receiving utomilumab in clinical 
studies, are listed in the following tables.  
Most Common Adverse Events (occurred in 10% or more of people  
taking utomilumab as a single agent, regardless of causality) 
 
Fatigue (30%)  
 
Nausea (21%)  
 
Appetite decreased (16%)  
 
Abdominal pain (14%)  
 
Fever (pyrexia) (14%)  
 
Vomiting (13%)  
 
Diarrhea (13%)  
 
Dizziness (12%)   
 
Anemia (12%)   
 
Constipation (12%)  
 
Labored breathing (dyspnea) (11%)  
 
Back pain (10%) 
The most commonly reported adverse events caused by utomilumab, reported in ≥ 10% of 
participants was fatigue (13%) (all grades).  Treatment-related AEs were mostly Grade 1 or 2 
with only five Grade 3/4 AEs reported (colitis;  diarrhea;  fatigue;  hyperbilirubinemia;  and 
hyponatremia).  No fatal treatment-related AEs were observed. 
There were 4 deaths during utomilumab treatment, caused by disease progression (3) and 
respiratory failure.  These deaths were not considered related to utomilumab. 
Most Common Adverse Events [occurred in 10% or more of people  
receiving utomilumab + rituximab (Rituxan), regardless of causality] 
 
Fatigue (27%)  
 
Infusion-related reaction (24%)  
 
Cough (18%)  
 
Headache (15%)  
 
Fever (pyrexia) (13%)  
 
Upper respiratory tract infection (13%)  
 
Diarrhea (12%) 
 
Blood creatinine increased (10%)  
 
Nausea (10%)  
 
Back pain (10%)  
 
Muscle pain (myalgia (10%) 
The most commonly reported adverse event caused by utomilumab + rituximab combination 
treatment was fatigue (9%).  Treatment-related AEs were mostly Grade 1 or Grade 2.  Two 
Grade 3 AEs were related to utomilumab (diarrhea and neutropenia).  Grade 3/4 AEs were 
limited to a single event of neutrophil count decreased.  No fatal treatment-related AEs were 
observed. 
There was 1 death during treatment, caused by disease progression.  This was not considered 
related to utomilumab. 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: George Sledge, MD   
Protocol Title:   
A Phase 1B Dose escalation Trial of Human Anti-4-1BB Agonistic 
Antibody utomilumab in Combination with Ado-trastuzumab Emtansine or 
Trastuzumab in Patients with Her2-positive Advanced Breast Cancer 
 
 
 
 
 
 
 
Sledge / IRB 37299 ICF 6 October 2020  
Page 9 of 28 
IRB Use Only 
Approval Date:   October 13, 2020 
Expiration Date: October 13, 2021 
Participant ID: 
Most Common Adverse Events [occurred in 10% or more of people  
receiving utomilumab + pembrolizumab (Keytruda), regardless of causality] 
23 study participants with solid tumors were treated with the combination of utomilumab and 
2 mg/kg pembrolizumab (Keytruda).  Utomilumab was administered at 0.45 mg/kg;  0.9 mg/kg;  
1.8 mg/kg;  3.6 mg/kg;  and 5 mg/kg.   
 
Fatigue (44%)  
 
Cough (35%)  
 
Nausea (35%)  
 
Decreased appetite (30%)  
 
Constipation (26%)  
 
Pruritus (26%)  
 
Rash maculo-papular (26%)  
 
Vomiting (26%)  
 
Anemia (22%)  
 
Pyrexia (22%)  
 
Back pain (17%)  
 
Dyspepsia (17%)  
 
Rash (17%)  
 
Upper respiratory tract infection (17%);   
 
Alanine aminotransferase increased (13%) 
 
Arthralgia (13%)  
 
Asthenia (13%)  
 
Dry mouth (13%)  
 
Dry skin (13%)  
 
Dyspnea (13%)  
 
Edema peripheral (13%)  
 
Fall (13%)  
 
Hemoptysis (13%)  
 
Hypokalemia (13%)  
 
Hyponatremia (13%)  
 
Muscle spasms (13%)  
 
Musculoskeletal chest pain (13%)  
 
Pleural effusion (13%)  
 
Pneumonia (13%)  
 
Sinusitis (13%)  
 
Stomatitis (13%) 
Most Common Treatment-related Adverse Events (occurred in 10% or more  
of people receiving utomilumab + pembrolizumab) 
 
Fatigue (35%)  
 
Rash maculo papular (26%)  
 
Pruritus (22%)  
 
Pyrexia (17%)  
 
Nausea (13%)  
 
Decreased appetite (13%)  
 
Dry skin (13%)  
 
Dry mouth (13%)  
Treatment-related AEs were mostly Grade 1 or Grade 2.  There were only 2 treatment-related 
Grade 3 AEs in participants receiving utomilumab + pembrolizumab combination treatment, 
adrenal insufficiency (1 participant) and hypokalemia (1 participant).  No life-threatening or fatal 
treatment-related AEs were observed. 
There was one Grade 5 AE (death) reported, (due to disease progression), which was 
considered not related to the study drug. 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: George Sledge, MD   
Protocol Title:   
A Phase 1B Dose escalation Trial of Human Anti-4-1BB Agonistic 
Antibody utomilumab in Combination with Ado-trastuzumab Emtansine or 
Trastuzumab in Patients with Her2-positive Advanced Breast Cancer 
 
 
 
 
 
 
 
Sledge / IRB 37299 ICF 6 October 2020  
Page 10 of 28 
IRB Use Only 
Approval Date:   October 13, 2020 
Expiration Date: October 13, 2021 
Participant ID: 
Most Common Adverse Events (occurred in 10% or more of people  
receiving utomilumab + mogamulizumab (Poteligeo), regardless of causality) 
48 study participants with solid tumors were treated with the combination of utomilumab and 
mogamulizumab (Poteligeo), with the participants receiving either 1 mg/kg or 2 mg/kg 
mogamulizumab (24 participants each).  Utomilumab was administered at 4 dose levels, 
1.2 mg/kg;  2.4 mg/kg;  5 mg/kg;  and 100 mg fixed dose. 
 
Fatigue (42%)  
 
Rash (29%)  
 
Constipation (21%) 
 
Nausea (21%) 
 
Diarrhea (21%) 
 
Pyrexia (21%)  
 
Appetite decreased (17%) 
 
Pruritus (17%) 
 
Anemia (17%) 
 
Dyspnea (17%) 
 
Headache (17%) 
 
Dreams abnormal (13%) 
 
Chills (13%) 
 
Cough (13%) 
 
Dehydration (13%) 
 
Infusion-related reaction (13%) 
 
Insomnia (13%) 
 
Lymphocyte count decreased (13%) 
 
Rhinorrhea (13%) 
Most Common Treatment-related Adverse Events (occurred in 10% or more  
of people receiving utomilumab + mogamulizumab) 
 
Fatigue (25%)  
 
Rash (25%)  
 
Diarrhea (21%)  
 
Nausea (21%)   
 
Pyrexia (21%)  
 
Abnormal dreams (13%) 
 
Infusion-related reaction (13%) 
 
Pruritus (13%) 
Most treatment-related TEAEs were Grade 1 or 2 in severity.  No Grade 5 treatment-related 
AEs were observed. 
There were no fatal 5 AEs reported in this study. 
Discontinuations Due to Adverse Events 
Utomilumab as a single agent  
15 adverse events reported in 13 participants that led to permanent discontinuation from 
treatment with utomilumab.  Only 1 participant (metastatic melanoma) treated at 1.2 mg/kg 
utomilumab permanently discontinued treatment with utomilumab, due to a Grade 2 AE of 
enterocolitis considered related to treatment.  
Utomilumab + mogamulizumab combination treatment 
1 participant permanently discontinued from treatment due to treatment-related Grade 3 
pneumonitis.  


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: George Sledge, MD   
Protocol Title:   
A Phase 1B Dose escalation Trial of Human Anti-4-1BB Agonistic 
Antibody utomilumab in Combination with Ado-trastuzumab Emtansine or 
Trastuzumab in Patients with Her2-positive Advanced Breast Cancer 
 
 
 
 
 
 
 
Sledge / IRB 37299 ICF 6 October 2020  
Page 11 of 28 
IRB Use Only 
Approval Date:   October 13, 2020 
Expiration Date: October 13, 2021 
Participant ID: 
Serious Adverse Events 
Utomilumab + rituximab combination treatment 
34 participants who received utomilumab in the utomilumab + rituximab combination study 
experienced 41 serious adverse events (SAEs) (regardless of causality), including 1 event each 
of colitis, diarrhea, enterocolitis, hyperbilirubinemia, decreased appetite, dehydration and 
pneumonitis that were considered treatment-related.  Utomilumab manufacturer Pfizer does not 
consider it a reasonable possibility that the event of hyperbilirubinemia was caused by 
utomilumab because of the presence of progressive disease (cancer metastases).  
Utomilumab + pembrolizumab combination treatment 
A total of 14 SAEs (all-causality) were reported in the safety database for 10 participants who 
received utomilumab and pembrolizumab.  None of these SAEs were considered related to 
utomilumab per Investigator assessment.  There was 1 SAE (Grade 2 inflammation) that was 
determined by the investigator as related to pembrolizumab treatment.  There was 1 SAE of 
special interest, a Grade 3 hyperbilirubinemia in the utomilumab 5 mg/kg + pembrolizumab 
2 mg/kg treatment group, which was considered not related to treatment. 
Utomilumab + mogamulizumab combination treatment 
10 participants in the utomilumab + mogamulizumab combination study experienced 13 serious 
adverse events (SAEs), none were considered treatment-related.  
Deaths on study 
13 participants died during the utomilumab plus rituximab trial, none of the events were 
considered related to utomilumab treatment. 
5 participants died during the utomilumab plus pembrolizumab trial, none of the events were 
considered related to utomilumab treatment. 
3 participants died during the utomilumab plus mogamulizumab trial, none of the events were 
considered related to utomilumab treatment. 
Grade 3 Laboratory Abnormalities (occurred in people taking  
utomilumab as a single agent, regardless of causality) 
 
Lymphopenia (19%)  
 
Hyponatremia (6%)  
 
Hypophosphatemia (4%)  
 
Anemia (3%)  
 
Hyperglycemia (3%)  
 
Alkaline phosphatase increased (2%)  
 
Hypokalemia (2%)  
 
Hypoalbuminemia (2%)  
 
Neutrophils, absolute count (ANC) (1%)  
 
Hypomagnesemia (1%)  
The only Grade 4 abnormal laboratory test abnormalities  were lymphopenia (2%), 
hypercalcemia (1%), and hypokalemia (1%). 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: George Sledge, MD   
Protocol Title:   
A Phase 1B Dose escalation Trial of Human Anti-4-1BB Agonistic 
Antibody utomilumab in Combination with Ado-trastuzumab Emtansine or 
Trastuzumab in Patients with Her2-positive Advanced Breast Cancer 
 
 
 
 
 
 
 
Sledge / IRB 37299 ICF 6 October 2020  
Page 12 of 28 
IRB Use Only 
Approval Date:   October 13, 2020 
Expiration Date: October 13, 2021 
Participant ID: 
Grade 3 Laboratory Abnormalities (occurred in people receiving  
utomilumab + rituximab, regardless of causality) 
 
Lymphopenia (35%)  
 
Neutrophil count decreased (6%)  
 
White blood cell (WBC) count decreased (5%)  
 
Hyperglycemia (4%)  
 
Hypophosphatemia (4%)  
 
Platelet count decreased (2%)  
 
ALT (liver enzyme) increased (2%) 
 
Hyperkalemia (2%) 
 
Hypomagnesemia   
 
Hypoglycemia (2%) 
 
Hyponatremia (2%) 
The only Grade 4 laboratory test abnormalities reported were lymphopenia (6%) and neutrophil 
count decreased (5%). 
Grade 3 Laboratory Abnormalities (occurred in people receiving  
utomilumab + pembrolizumab, regardless of causality) 
 
Lymphopenia (26%)  
 
Anemia (13%)  
 
Hypoalbuminemia (13%)  
 
Hyponatremia (13.0%)  
 
Hyperglycemia (9%)  
 
Hypokalemia (9%)  
 
Hypophosphatemia (9%)  
 
Bilirubin increased (considered related) (4%)  
The only Grade 3 laboratory test abnormality that was considered related to treatment was 
Alkaline phosphatase increased (4%). 
The only Grade 4 laboratory test abnormalities reported were lymphopenia (4.3%) and 
hyponatremia (4.3%).   
Grade 3 Laboratory Abnormalities (occurred in people receiving  
utomilumab + mogamulizumab, regardless of causality) 
 
Lymphopenia (29%)  
 
Hyperglycemia (13%)  
 
Anemia (8%)  
 
Hypophosphatemia (8%)  
 
Hyponatremia (4%)  
The only Grade 4 laboratory test abnormalities reported was lymphopenia (4%). 
Antibodies to Utomilumab  
A small number of patients receiving utomilumab treatment developed antibodies to 
utomilumab.  Some patients have antibodies at baseline, ie, before utomilumab treatment.  
The clinical significance of antibodies to utomilumab is unclear.  In some instances, these 
antibodies may be pre-existing against other biological entities.  No serious or significant 
clinical effects have been observed, including that the presence of antibodies to utomilumab 
did not affect response to combination treatment.  


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: George Sledge, MD   
Protocol Title:   
A Phase 1B Dose escalation Trial of Human Anti-4-1BB Agonistic 
Antibody utomilumab in Combination with Ado-trastuzumab Emtansine or 
Trastuzumab in Patients with Her2-positive Advanced Breast Cancer 
 
 
 
 
 
 
 
Sledge / IRB 37299 ICF 6 October 2020  
Page 13 of 28 
IRB Use Only 
Approval Date:   October 13, 2020 
Expiration Date: October 13, 2021 
Participant ID: 
Potential side effects of Ado-trastuzumab emtansine (Kadcyla, T-DM1)  
Ado-trastuzumab emtansine (Kadcyla, T-DM1) is an FDA-approved drug.  The drug package 
insert for this product provides a complete listing of warnings and precautions.   
 
Most Common Grade 1 to 2 (mild to moderate) Side Effects  
(occurred in more than 20% of people taking T-DM1)  
 
Upset stomach (nausea) 
 
Tiredness (fatigue)  
 
Body pain (musculoskeletal pain) 
 
Bleeding (hemorrhage)  
 
Decrease in blood levels of platelets, may 
cause bleeding or bruising  
(thrombocytopenia)  
 
Increased blood levels of liver enzymes 
(increased transaminases) 
 
Headache  
 
Constipation  
 
Diarrhea  
 
Bloody nose (epistaxis)  
 
Numbness, pain, or weakness, usually in 
hands and feet (peripheral neuropathy)  
 
Less-likely Grade 1 to 2 Side Effects  
(occurred in more than 10% to 20% of people taking T-DM1)  
 
Vomiting  
 
Joint pain (arthralgia)  
 
Abdominal pain  
 
Fever (pyrexia)   
 
Cough  
 
Physical weakness or lack of energy 
(asthenia)   
 
Dry Mouth  
 
Decreased levels of red blood cells may 
cause tiredness and fatigue (anemia)   
 
Soreness and inflammation of the mouth, 
may affect eating, talking and sleeping 
(stomatitis)   
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: George Sledge, MD   
Protocol Title:   
A Phase 1B Dose escalation Trial of Human Anti-4-1BB Agonistic 
Antibody utomilumab in Combination with Ado-trastuzumab Emtansine or 
Trastuzumab in Patients with Her2-positive Advanced Breast Cancer 
 
 
 
 
 
 
 
Sledge / IRB 37299 ICF 6 October 2020  
Page 14 of 28 
IRB Use Only 
Approval Date:   October 13, 2020 
Expiration Date: October 13, 2021 
Participant ID: 
Unlikely Grade 1 to 2 Side Effects  
(these side effects occurred in 1% to 10% of people taking T-DM1) 
 
Urinary tract infection  
 
Indigestion, including abdominal fullness, 
heartburn, nausea, belching (dyspepsia)   
 
Bad taste in the mouth (dysgeusia)   
 
Chills  
 
Swelling in the limbs (peripheral edema)   
 
Decreased levels of neutrophils, a type of 
infection-fighting cell (neutropenia)  
 
Rash or itching (pruritus)  
 
Increased blood pressure (hypertension)  
 
Increased blood level of alkaline 
phosphatase  
 
Vision blurred  
 
Dry eye  
 
Eye infection, “pink eye” (conjunctivitis)  
 
Increased tear production (lacrimation 
increased) 
 
Increased sensitivity to other drugs (drug 
hypersensitivity)  
 
Heart problems (left ventricular 
dysfunction)  
 
Infusion-related reaction, can include 
flushing, rash, fever, rigors, chills, difficulty 
breathing, decreased blood pressure, or 
heart problems  
 
Inflammation in the lungs (pneumonitis) 
 
Grade 3 to 4 (severe or life-threatening) adverse events (these side effects occurred in 
1 to 15% of people taking T-DM1) 
 
Decrease in blood levels of platelets, may 
cause bleeding or bruising  
(thrombocytopenia)  
 
Increased blood levels of liver enzymes 
(increased transaminases) 
 
Decreased levels of red blood cells may 
cause tiredness and fatigue (anemia)   
 
Decreased levels of potassium in the blood 
(hypokalemia)   
 
Tiredness (fatigue)  
 
Numbness, pain, or weakness, usually in 
hands and feet (peripheral neuropathy)  
 
Decreased levels of neutrophils, a type of 
infection-fighting cell (neutropenia)  
 
Body pain (musculoskeletal pain) 
 
Bleeding (hemorrhage)  
 
Diarrhea  
 
Increased blood pressure (hypertension)  
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: George Sledge, MD   
Protocol Title:   
A Phase 1B Dose escalation Trial of Human Anti-4-1BB Agonistic 
Antibody utomilumab in Combination with Ado-trastuzumab Emtansine or 
Trastuzumab in Patients with Her2-positive Advanced Breast Cancer 
 
 
 
 
 
 
 
Sledge / IRB 37299 ICF 6 October 2020  
Page 15 of 28 
IRB Use Only 
Approval Date:   October 13, 2020 
Expiration Date: October 13, 2021 
Participant ID: 
Rare but Serious / Severe Side Effects  
(these side effects occurred in less than 1% of people taking T-DM1)  
 
Abdominal pain  
 
Vomiting  
 
Upset stomach (nausea) 
 
Headache  
 
Shortness of breath;  unpleasant;  or 
uncomfortable breathing (dyspnea)   
 
Urinary tract infection  
 
Muscle pain (myalgia)   
 
Joint pain (arthralgia)  
 
Constipation  
 
Physical weakness or lack of energy 
(asthenia)   
 
Increased blood level of alkaline phosphatase  
 
Dizziness  
 
Difficulty sleeping (insomnia)   
 
Heart problems (left ventricular dysfunction)  
 
Soreness and inflammation of the mouth, may 
affect eating, talking and sleeping (stomatitis)   
 
Fever (pyrexia)   
 
Increase in the blood pressure in the liver and 
other internal organs (portal hypertension)  
 
Cough  
 
Bloody nose (epistaxis)  
 
Rash or itching (pruritus)  
Specific Warnings for T-DM1  
Liver toxicity 
Liver toxicity, usually elevated levels of liver enzymes in the blood, have occurred.  Serious liver 
toxicity, including at least two fatal cases of severe drug-induced liver injury have been reported.  
Heart toxicity 
People treated with T-DM1 are at increased risk of developing a specific kind of heart problem, 
called left ventricular dysfunction, although this may be more or less than the amount observed 
with other treatments.  
Lung Toxicity 
Lung problems, some leading to acute respiratory distress syndrome or death have been 
reported in clinical trials with T-DM1.  Patients with breathing difficulties may be at increased 
risk. 
Infusion-related reactions 
At least one case of anaphylaxis, a serious allergic reaction, has occurred in a patient receiving 
single-agent T-DM1.  Anaphylaxis can be fatal.  
Hemorrhage 
Cases of hemorrhagic events, including in the brain and central nervous system, lungs, and 
gastrointestinal track, have been reported, some bleeding events were fatal. 
Decreased levels of platelets 
Decreased platelet count (thrombocytopenia) was reported over 30% of people receiving 
T-DM1, most events were mild to moderate (Grade 1 to 2).  The incidence and severity of 
thrombocytopenia may higher in Asian patients.  


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: George Sledge, MD   
Protocol Title:   
A Phase 1B Dose escalation Trial of Human Anti-4-1BB Agonistic 
Antibody utomilumab in Combination with Ado-trastuzumab Emtansine or 
Trastuzumab in Patients with Her2-positive Advanced Breast Cancer 
 
 
 
 
 
 
 
Sledge / IRB 37299 ICF 6 October 2020  
Page 16 of 28 
IRB Use Only 
Approval Date:   October 13, 2020 
Expiration Date: October 13, 2021 
Participant ID: 
Nerve toxicity 
Nerve toxicity in the limbs, hands and feet (peripheral neuropathy) has been reported in over 
20% of people receiving T-DM1.  The events were mainly mild (Grade 1), but can be severe or 
worse.   
Effects on pregnancy 
T-DM1 can cause fetal harm when administered to a pregnant woman.  
Risks and possible discomforts you might experience from the study procedures 
include: 
Risks of the Blood Collection and IV 
You may have pain, swelling, or bruising around the vein where your blood is collected/IV 
inserted.  There may be risk of infection.  You may feel dizzy or you may faint.  You may get an 
infection at the place on your body from which the blood is collected and/or IV insertion.   
Risks of the ECG  
Placement of the leads may cause skin irritation, redness, or burning of the skin at the site 
where the leads were attached. 
Risks of the CT Scan 
When the contrast medium is injected during the CT scan, you may experience nausea, 
flushing, warmth and a salty taste.  You might be allergic to the contrast medium.  You must not 
move during the test, but relax and breathe normally.  You might be uncomfortable while you 
are in the tunnel-shaped machine.  Some subjects have felt claustrophobic during this test.   
This research study involves exposure to radiation from up to two CT scans.  This radiation 
exposure is not necessary for your medical care and is for research purposes only.  The 
additional amount of radiation exposure is about 30 mSv, which is approximately equal to 60% 
of the limit that radiation workers (for example, a hospital X-ray technician) are allowed to 
receive in 1 year.  This amount of radiation involves minimal risk and is necessary to obtain the 
research information desired. 
Risks of MRI 
MRI (Magnetic Resonance Imaging) 
MRI machines use a strong magnet and radiofrequency magnetic fields to make images of the 
body interior.  The scanning procedure is very much like an X-ray or CT scan.  You will be asked 
to lie on a long narrow couch for a certain amount of time approximately 30 to 60 minutes while 
the machine gathers data.  During this time you will not be exposed to X-rays, but rather a strong 
magnetic field and radiofrequency magnetic fields, which you will not feel.  You will, however, 
hear repetitive tapping noises that arise from the Magnetic Resonance scanner.  We will provide 
earplugs or headphones that you will be required to wear.  The space within the large magnet in 
which you lie is somewhat confined, although we have taken many steps to relieve the 
"claustrophobic" feeling. 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: George Sledge, MD   
Protocol Title:   
A Phase 1B Dose escalation Trial of Human Anti-4-1BB Agonistic 
Antibody utomilumab in Combination with Ado-trastuzumab Emtansine or 
Trastuzumab in Patients with Her2-positive Advanced Breast Cancer 
 
 
 
 
 
 
 
Sledge / IRB 37299 ICF 6 October 2020  
Page 17 of 28 
IRB Use Only 
Approval Date:   October 13, 2020 
Expiration Date: October 13, 2021 
Participant ID: 
Risks: 
Magnetic fields do not cause harmful effects at the levels used in the MRI machine.  However, the 
MR scanner uses a very strong magnet that will attract some metals and affect some electronic 
devices.  If you have a cardiac pacemaker or any other biomedical device in or on your body, it is 
very important that you tell the operator/investigator immediately.  As metallic objects may 
experience a strong attraction to the magnet, it is also very important that you notify the operator 
of any metal objects (especially surgical clips), devices, or implants that are in or on your body 
before entering the magnet room.  All such objects must be removed (if possible) before entering 
the magnet room.  In some cases, having those devices means you should not have an MRI scan 
performed.  In addition, watches and credit cards should also be removed as these could be 
damaged.   
o If you have an artificial heart valve; a pacemaker; or any other biomedical device in or on 
your body, these devices could malfunction when exposed to the very strong magnetic field.  
o If you have a metal plate; pin; screws; surgical clips; metallic fragments; or any other 
metallic implant in your body, these pieces of metal could move while in your body, causing 
possible serious injury or death.  
o If you have tattoos, these could become warm and irritated during the scan and remain so 
for several days.  
If you have a history of severe allergies (eg, bee-sting reaction, food, shellfish, or nut reactions), 
or have previously had a reaction to medications or contrast agents, in particular 
Gadolinium-based contrast agents, you may be at risk of a serious reaction, which can be severe 
and/or life-threatening, including breathing difficulty;  sweating;  numbness;  or heart palpitations.  
Tell the study team or technician immediately if you experience these.   
It has been observed that deposits of Gadolinium-based contrast agent (GBCA) remain in the 
brains of some people who undergo four or more contrast enhanced MRI scans, long after the 
last administration. It is not yet known whether these Gadolinium deposits are harmful or can lead 
to adverse health effects.  You should talk to the study doctor if you have any questions about the 
use of GBCAs with MRIs. 
IF YOU FEEL DISCOMFORT AT ANY TIME, NOTIFY THE OPERATOR AND YOU CAN 
DISCONTINUE THE EXAM AT ANY TIME. 
Pregnancy Related Risks / Use of Birth Control 
The effects of utomilumab on sperm, a pregnancy, or a nursing child are not known.  The study 
doctor will instruct you in the correct use of your selected birth control methods and how to use 
them consistently and correctly. 
Women of Childbearing Potential 
If you are a woman who is able to become pregnant, it is expected that you will use two effective 
methods of birth control consistently and correctly during and for 60 days after you have stopped 
taking the study drug to prevent exposing a fetus to a potentially dangerous agent with unknown 
risk.  If you are currently pregnant, planning to become pregnant or father a child, you should not 
take part in this study.  You understand that if you are pregnant, if you become pregnant, or if you 
are breast-feeding during this study, you or your child may be exposed to an unknown risk. 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: George Sledge, MD   
Protocol Title:   
A Phase 1B Dose escalation Trial of Human Anti-4-1BB Agonistic 
Antibody utomilumab in Combination with Ado-trastuzumab Emtansine or 
Trastuzumab in Patients with Her2-positive Advanced Breast Cancer 
 
 
 
 
 
 
 
Sledge / IRB 37299 ICF 6 October 2020  
Page 18 of 28 
IRB Use Only 
Approval Date:   October 13, 2020 
Expiration Date: October 13, 2021 
Participant ID: 
To confirm to the extent medically possible that you are not pregnant, you agree to have a 
pregnancy test done before beginning this research study.  You must agree to avoid sexual 
intercourse or use a birth control method judged to be effective by the investigator and which will 
not interfere with the proposed investigation.  You must accept the risk that pregnancy could still 
result despite the responsible use of reliable methods of birth control.  You agree to notify the 
investigator as soon as possible of any failure of proper use of your birth control method, or if you 
become pregnant, either of which may result in your being withdrawn from the study. 
Birth control methods, even when used consistently and correctly, are not perfect.  If you 
become pregnant during the study or you want to stop your required birth control during the 
study, you should tell your doctor immediately.  You may be withdrawn for safety reasons if you 
discontinue birth control or you become pregnant. 
If you are a man participating in this study and your partner is able to become pregnant, you and 
your partner must use adequate contraception while you are participating in the study and for at 
least 90 days after you stop taking the study medication.  Your doctor will discuss with you what 
methods of birth control are considered adequate.   
POTENTIAL BENEFITS  
It is possible that your condition or health may improve because of study treatment or because 
of your visits to the research site.  Information from this study may benefit others in the future.  
We cannot and do not guarantee or promise that you will receive any benefits from this 
study. 
ALTERNATIVES 
You do not have to be in this study to receive treatment for your cancer.  Instead of taking part 
in this study, you may choose to receive treatment with other anti-cancer drugs and/or surgery 
that have been approved for use in this country.  Your study doctor will be able to discuss 
alternative treatments and their risks/benefits with you. 
PARTICIPANT’S RIGHTS 
You should not feel obligated to agree to participate.  Your questions should be answered 
clearly and to your satisfaction.  If you decide not to participate, tell the Protocol Director.   
You will be told of any important new information that is learned during the course of this 
research study, which might affect your condition or your willingness to continue participation in 
this study. 
ClinicalTrials.gov 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
US Law.  This Web site will not include information that can identify you.  At most, the Web site 
will include a summary of the results.  You can search this Web site at any time. 
The description of this clinical trial is at https://clinicaltrials.gov/ct2/show/NCT03364348. 
CONFIDENTIALITY 
The results of this research study may be presented at scientific or medical meetings or 
published in scientific journals.  Your identity and/or your personal health information will not be 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: George Sledge, MD   
Protocol Title:   
A Phase 1B Dose escalation Trial of Human Anti-4-1BB Agonistic 
Antibody utomilumab in Combination with Ado-trastuzumab Emtansine or 
Trastuzumab in Patients with Her2-positive Advanced Breast Cancer 
 
 
 
 
 
 
 
Sledge / IRB 37299 ICF 6 October 2020  
Page 19 of 28 
IRB Use Only 
Approval Date:   October 13, 2020 
Expiration Date: October 13, 2021 
Participant ID: 
disclosed except as authorized by you or as required by law.  However, there is always some 
risk that even de-identified information might be re-identified.   
Patient information may be provided to Federal and other regulatory agencies as required.  The 
Food and Drug Administration (FDA), for example, may inspect research records and learn your 
identity if this study falls within its jurisdiction. 
The purpose of this research study is to obtain data or information on the safety and 
effectiveness of utomilumab alone or in combination with ado-trastuzumab emtansine or 
trastuzumab.  The results will be provided to the sponsor, the Food and Drug Administration and 
other federal and regulatory agencies as required. 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: George Sledge, MD   
Protocol Title:   
A Phase 1B Dose escalation Trial of Human Anti-4-1BB Agonistic 
Antibody utomilumab in Combination with Ado-trastuzumab Emtansine or 
Trastuzumab in Patients with Her2-positive Advanced Breast Cancer 
 
 
 
 
 
 
 
Sledge / IRB 37299 ICF 6 October 2020  
Page 20 of 28 
IRB Use Only 
Approval Date:   October 13, 2020 
Expiration Date: October 13, 2021 
Participant ID: 
Authorization to Use Your Health Information for Research Purposes 
Because information about you and your health is personal and private, it 
generally cannot be used in this research study without your written 
authorization.  If you sign this form, it will provide that authorization.  The 
form is intended to inform you about how your health information will be 
used or disclosed in the study.  Your information will only be used in 
accordance with this authorization form and the informed consent form and 
as required or allowed by law.  Please read it carefully before signing it.   
What is the purpose of this research study and how will my health 
information be utilized in the study? 
The purpose of this research study is to learn about the effects of the safety 
and effectiveness of utomilumab alone or in combination with 
ado-trastuzumab emtansine or trastuzumab and to find the best dose for 
treating advanced breast cancer.   
Your health records will be used to gather information about your disease, 
your response to the treatment and any side effects that may occur.  The 
information obtained from this study may be used in a publication or an 
application to the FDA for approval of this drug. 
In addition, during and after your participation in the study your study doctor 
will be required to report to the sponsor information related to any serious 
adverse effect that you may experience due to your participation in the 
study. 
Do I have to sign this authorization form? 
You do not have to sign this authorization form.  But if you do not, you will 
not be able to participate in this research study including receiving any 
research-related treatment.  Signing the form is not a condition for receiving 
any medical care outside the study. 
If I sign, can I revoke it or withdraw from the research later? 
If you decide to participate, you are free to withdraw your authorization 
regarding the use and disclosure of your health information (and to 
discontinue any other participation in the study) at any time.  After any 
revocation, your health information will no longer be used or disclosed in 
the study, except to the extent that the law allows us to continue using your 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: George Sledge, MD   
Protocol Title:   
A Phase 1B Dose escalation Trial of Human Anti-4-1BB Agonistic 
Antibody utomilumab in Combination with Ado-trastuzumab Emtansine or 
Trastuzumab in Patients with Her2-positive Advanced Breast Cancer 
 
 
 
 
 
 
 
Sledge / IRB 37299 ICF 6 October 2020  
Page 21 of 28 
IRB Use Only 
Approval Date:   October 13, 2020 
Expiration Date: October 13, 2021 
Participant ID: 
information (eg, necessary to maintain integrity of research).  If you wish to 
revoke your authorization for the research use or disclosure of your health 
information in this study, you must write to:  Dr. George Sledge, Stanford 
University Medical Center, 269 Campus Drive, CCSR, Room 1115, 
Stanford, CA 94305, telephone XXX-XXX-XXXX.   
What Personal Information Will Be Used or Disclosed? 
You will be identified by name, medical record number, address, telephone 
number, and other direct personal identifiers to persons directly involved 
with your medical care and to those involved in the conduct and monitoring 
of the study.  Your health information related to this study, may be used or 
disclosed in connection with this research study, including, but not limited 
to, blood and other tissue samples and related records, physical 
examinations, CT scans, MRIs and other diagnostic test results. 
Who May Use or Disclose the Information? 
The following parties are authorized to use and/or disclose your health 
information in connection with this research study: 
 The Protocol Director, Dr. George Sledge and his associates at 
Stanford Medical Center who are involved in your medical care 
including study coordinators, research nurses and clinic and 
laboratory employees. 
 The Stanford University Administrative Panel on Human Subjects in 
Medical Research and any other unit of Stanford University as 
necessary 
 Other research personnel at Stanford University and Medical Center. 
Who May Receive or Use the Information? 
The parties listed in the preceding paragraph may disclose your health 
information to the following persons and organizations for their use in 
connection with this research study:  
 The Office for Human Research Protections in the US Department of 
Health and Human Services 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: George Sledge, MD   
Protocol Title:   
A Phase 1B Dose escalation Trial of Human Anti-4-1BB Agonistic 
Antibody utomilumab in Combination with Ado-trastuzumab Emtansine or 
Trastuzumab in Patients with Her2-positive Advanced Breast Cancer 
 
 
 
 
 
 
 
Sledge / IRB 37299 ICF 6 October 2020  
Page 22 of 28 
IRB Use Only 
Approval Date:   October 13, 2020 
Expiration Date: October 13, 2021 
Participant ID: 
 Government health agencies (such as the Food and Drug 
Administration and the National Institute of Health) in the US or other 
countries 
 Pfizer Inc, the manufacturer of the study drug.   
 The Food and Drug Administration 
 Researchers who are conducting this study at other research sites  
Your information may be re-disclosed by the recipients described above, if 
they are not required by law to protect the privacy of the information. 
When will my authorization expire? 
Your authorization for the use and/or disclosure of your health information 
will end on December 31, 2050 or when the research project ends, 
whichever is earlier. 
Will access to my medical record be limited during the study? 
To maintain the integrity of this research study, you may not have access to 
any health information developed as part of this study until it is completed.  
At that point, you would have access to such health information if it was 
used to make a medical or billing decision about you (eg, if included in your 
official medical record).   
 
________________________________             
______________ 
Signature of Adult Participant                                   Date 
 
________________________________ 
Print Name of Participant 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: George Sledge, MD   
Protocol Title:   
A Phase 1B Dose escalation Trial of Human Anti-4-1BB Agonistic 
Antibody utomilumab in Combination with Ado-trastuzumab Emtansine or 
Trastuzumab in Patients with Her2-positive Advanced Breast Cancer 
 
 
 
 
 
 
 
Sledge / IRB 37299 ICF 6 October 2020  
Page 23 of 28 
IRB Use Only 
Approval Date:   October 13, 2020 
Expiration Date: October 13, 2021 
Participant ID: 
 
 
_______________________________                     
 
_________ 
Signature of Legally Authorized Representative (LAR)           
    Date 
(eg, parent, guardian or conservator) 
 
 
_______________________________ 
Print Name of LAR 
 
 
________________________________________________________ 
LAR’s Authority to Act for Participant 
(eg, parent, guardian or conservator) 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: George Sledge, MD   
Protocol Title:   
A Phase 1B Dose escalation Trial of Human Anti-4-1BB Agonistic 
Antibody utomilumab in Combination with Ado-trastuzumab Emtansine or 
Trastuzumab in Patients with Her2-positive Advanced Breast Cancer 
 
 
 
 
 
 
 
Sledge / IRB 37299 ICF 6 October 2020  
Page 24 of 28 
IRB Use Only 
Approval Date:   October 13, 2020 
Expiration Date: October 13, 2021 
Participant ID: 
FINANCIAL CONSIDERATIONS 
Payment 
You will not be paid to participate in this research study.   
Costs 
If you participate in this study, the study will pay for those services, supplies, procedures, and 
care associated with the study that are not a part of your routine medical care.  However, there 
may be additional costs to you.  These include basic expenses like transportation and the 
personal time it will take to come to the study visits.  You and/or your health insurance must pay 
for services, supplies, procedures, and care that are required during this study for routine 
medical care.  You will also be responsible for any co-payments and/or deductibles as 
required by your insurance.  Participation in this study is not a substitute for health insurance.   
Pfizer is providing financial support and material for this study.  The study drug, utomilumab will 
be provided free of charge while you are participating in this study.   
The National Institutes of Health are providing some financial support for the facility and staff 
where part or all of the study is taking place. 
COMPENSATION for Research-Related Injury  
All forms of medical diagnosis and treatment – whether routine or experimental – involve some 
risk of injury.  In spite of all precautions, you might develop medical complications from 
participating in this study.  If such complications arise, the Protocol Director and the research 
study staff will assist you in obtaining appropriate medical treatment.  In the event that you have 
an injury or illness that is directly caused by your participation in this study, reimbursement for 
all related costs of care first will be sought from your insurer, managed care plan, or other 
benefits program.  You will be responsible for any associated co-payments or deductibles 
as required by your insurance. 
If costs of care related to such an injury are not covered by your insurer, managed care plan or 
other benefits program, you may be responsible for these costs.  If you are unable to pay for 
such costs, the Protocol Director will assist you in applying for supplemental benefits and 
explain how to apply for patient financial assistance from the hospital. 
You do not waive any liability rights for personal injury by signing this form. 
Consultative or Financial Relationships   
Dr. Melinda Telli is a paid advisor to Pfizer Pharmaceuticals, the company sponsoring this 
research study. 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: George Sledge, MD   
Protocol Title:   
A Phase 1B Dose escalation Trial of Human Anti-4-1BB Agonistic 
Antibody utomilumab in Combination with Ado-trastuzumab Emtansine or 
Trastuzumab in Patients with Her2-positive Advanced Breast Cancer 
 
 
 
 
 
 
 
Sledge / IRB 37299 ICF 6 October 2020  
Page 25 of 28 
IRB Use Only 
Approval Date:   October 13, 2020 
Expiration Date: October 13, 2021 
Participant ID: 
CONTACT INFORMATION  
Questions, Concerns, or Complaints:  If you have any questions, concerns or complaints about 
this research study, its procedures, risks and benefits, or alternative courses of treatment, you 
should ask the Protocol Director, George Sledge, MD, at XXX-XXX-XXXX.  You should also 
contact him at any time if you feel you have been hurt by being a part of this study.   
Independent Contact:  If you are not satisfied with how this study is being conducted, or if you 
have any concerns, complaints, or general questions about the research or your rights as a 
participant, please contact the Stanford Institutional Review Board (IRB) to speak to someone 
independent of the research team at XXX-XXX-XXXX or toll free at XXX-XXX-XXXX.  You can 
also write to the Stanford IRB, Stanford University, 1705 El Camino Real, Palo Alto, CA  94306. 
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: George Sledge, MD   
Protocol Title:   
A Phase 1B Dose escalation Trial of Human Anti-4-1BB Agonistic 
Antibody utomilumab in Combination with Ado-trastuzumab Emtansine or 
Trastuzumab in Patients with Her2-positive Advanced Breast Cancer 
 
 
 
 
 
 
 
Sledge / IRB 37299 ICF 6 October 2020  
Page 26 of 28 
IRB Use Only 
Approval Date:   October 13, 2020 
Expiration Date: October 13, 2021 
Participant ID: 
EXPERIMENTAL SUBJECT’S BILL OF RIGHTS 
As a research participant you have the following rights.  These rights include but are not 
limited to the participant's right to: 
 
be informed of the nature and purpose of the experiment;  
 
be given an explanation of the procedures to be followed in the medical 
experiment, and any drug or device to be utilized;  
 
be given a description of any attendant discomforts and risks reasonably to be 
expected;  
 
be given an explanation of any benefits to the subject reasonably to be expected, 
if applicable;  
 
be given a disclosure of any appropriate alternatives, drugs or devices that might 
be advantageous to the subject, their relative risks and benefits; 
 
be informed of the avenues of medical treatment, if any available to the subject 
after the experiment if complications should arise;  
 
be given an opportunity to ask questions concerning the experiment or the 
procedures involved;  
 
be instructed that consent to participate in the medical experiment may be 
withdrawn at any time and the subject may discontinue participation without 
prejudice;  
 
be given a copy of the signed and dated consent form; and  
 
be given the opportunity to decide to consent or not to consent to a medical 
experiment without the intervention of any element of force, fraud, deceit, duress, 
coercion or undue influence on the subject's decision. 
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: George Sledge, MD   
Protocol Title:   
A Phase 1B Dose escalation Trial of Human Anti-4-1BB Agonistic 
Antibody utomilumab in Combination with Ado-trastuzumab Emtansine or 
Trastuzumab in Patients with Her2-positive Advanced Breast Cancer 
 
 
 
 
 
 
 
Sledge / IRB 37299 ICF 6 October 2020  
Page 27 of 28 
IRB Use Only 
Approval Date:   October 13, 2020 
Expiration Date: October 13, 2021 
Participant ID: 
Signing your name means you agree to be in this study and that you were given a copy of this 
signed and dated consent form.   
 
 
 
Signature of Adult Participant 
 
Date 
 
 
 
 
Print Name of Adult Participant 
 
 
 
 
 
 
 
 
Signature of Legally Authorized Representative 
(LAR) (eg, parent, guardian or conservator) 
 
Date 
 
 
 
 
Print Name of LAR 
 
 
 
 
 
 
LAR’s Authority to Act for Participant (eg, parent, 
guardian, or conservator) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Person Obtaining Consent  
 
 
__________________________________________ 
Print Name of Person Obtaining Consent 
 
Date 
 
 
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: George Sledge, MD   
Protocol Title:   
A Phase 1B Dose escalation Trial of Human Anti-4-1BB Agonistic 
Antibody utomilumab in Combination with Ado-trastuzumab Emtansine or 
Trastuzumab in Patients with Her2-positive Advanced Breast Cancer 
 
 
 
 
 
 
 
Sledge / IRB 37299 ICF 6 October 2020  
Page 28 of 28 
IRB Use Only 
Approval Date:   October 13, 2020 
Expiration Date: October 13, 2021 
Participant ID: 
The following witness line is to be signed only if the consent is provided as a summary form and 
accompanied by a short form foreign language consent. 
 
 
 
 
Signature of Witness 
 
_______________________________ 
Print Name of Witness 
 
Date 
 
 
(eg, staff, translator/interpreter, family member) 
 
 Translated short form must be signed and dated by both the participant (or their LAR) AND 
the witness. 
 The English consent form (referred to as the "Summary Form" in the regulations): 
 Must be signed by the witness AND the Person Obtaining Consent (POC). 
 The non-English speaking participant/LAR does not sign the English consent. 
 The non-English speaking participant/LAR should not sign the HIPAA participant line 
 If the participant or the LAR is non-English speaking, the Person Obtaining Consent (POC) 
must ensure that 1) the LAR's Description of Authority is completed and 2) that any 
questions or options presented by the consent form are documented and initialed by the 
POC on the Summary Form, per the participant's wishes, as they are understood during the 
consent process.