Clinical trial NCT03558139
Conditions: Ovarian Cancer
Sponsor: Gilead Sciences
Start date: 2018-05-23; Completion date: 2020-12-03
Enrollment: 34 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The primary objectives of this study are to investigate the safety and tolerability of magrolimab in combination with avelumab in participants with advanced solid tumors and to confirm the safety and tolerability of this combination and evaluate the anti-tumor activity in participants with checkpoint inhibitor-naive ovarian cancer, fallopian tube cancer, and primary peritoneal carcinoma who have previously progressed within 1-6 months of receiving platinum chemotherapy.

Detailed description:

Arms: arm 1: Participants with solid tumors will be treated with starting priming dose of 1 mg/kg of body weight magrolimab IV infusion (over 3 hours) on Day 1 of Cycle 1 followed by maintenance dose of 30 mg/kg of body weight magrolimab IV infusion (over 2 hours) on Days 8, 15, 22, and 29 of Cycle 1 and Days 1 and 15 of Cycle 2 and subsequent cycles, in combination with 800 mg avelumab IV infusion (over 1 hour) on Days 8 and 22 of Cycle 1 and Days 1 and 15 of Cycle 2 and subsequent cycles.

Cycle 1 will consist of 35 days and Cycle 2 and subsequent cycle will consist of 28 days. Avelumab will be administered 1 hour prior to magrolimab infusion on days when both are given. Treatment will be administered until confirmed tumor progression, unacceptable toxicity, clinically significant change in the participant's status that precluded further treatment, voluntary withdrawal, or physician decision. arm 2: Participants with solid tumors will be treated with starting priming dose of 1 mg/kg of body weight magrolimab IV infusion (over 3 hours) on Day 1 of Cycle 1 followed by maintenance dose of 45 mg/kg of body weight magrolimab IV infusion (over 2 hours) on Days 8, 11, 15, 22, and 29 of Cycle 1; Days 1, 8, 15 and 22 of Cycle 2 and Days 1 and 15 of subsequent cycles, in combination with 800 mg avelumab IV infusion (over 1 hour) on Days 8 and 22 of Cycle 1 and Days 1 and 15 of Cycle 2 and subsequent cycles.

Cycle 1 will consist of 35 days and Cycle 2 and subsequent cycle will consist of 28 days. Avelumab will be administered 1 hour prior to magrolimab infusion on days when both are given. Treatment will be administered until confirmed tumor progression, unacceptable toxicity, clinically significant change in the participant's status that precluded further treatment, voluntary withdrawal, or physician decision. arm 3: Participants with checkpoint inhibitor-naïve ovarian cancer will be treated with starting priming dose of 1 mg/kg of body weight magrolimab IV infusion (over 3 hours) on Day 1 of Cycle 1 followed by maintenance dose of 45 mg/kg of body weight magrolimab IV infusion (over 2 hours) on Days 8, 11, 15, 22, and 29 of Cycle 1; Days 1, 8, 15 and 22 of Cycle 2 and Days 1 and 15 of subsequent cycles, in combination with 800 mg avelumab IV infusion (over 1 hour) on Days 8 and 22 of Cycle 1 and Days 1 and 15 of Cycle 2 and subsequent cycles.

Cycle 1 will consist of 35 days and Cycle 2 and subsequent cycle will consist of 28 days. Avelumab will be administered 1 hour prior to magrolimab infusion on days when both are given. Treatment will be administered until confirmed tumor progression, unacceptable toxicity, clinically significant change in the participant's status that precluded further treatment, voluntary withdrawal, or physician decision.
Interventions: intervention 1: Magrolimab intervention 2: Avelumab
Intervention descriptions: intervention 1: Administered intravenously intervention 2: Administered intravenously

Protocol documents:
Prot_000.pdf: 
Hu5F9-G4 
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CLINICAL STUDY PROTOCOL 
Protocol Title: 
A Phase 1b Trial of Hu5F9-G4 in Combination with Avelumab 
in Solid Tumor Patients and Checkpoint-lnhibitor-Na'ive 
Ovarian Cancer Patients Who Progress within 6 Months of 
Prior Platinum Chemotherapy 
Protocol Number: 
5F9006 
lnvestigational Medicinal 
Hu5F9-G4 in combination with avelumab 
Product: 
Indication: 
Ovarian cancer 
Development Phase: 
1b 
US IND Number: 
136624 
EudraCT Number: 
NA 
Sponsor: 
Forty Seven Inc. 
1490 O'Brien Drive, Suite A 
Menlo Park, CA 94025 USA 
Telephone: IPPD 
Fax: PPD 
Medical Monitor: 
PPD 
~ eleph~
.PlJ 
Email: IPPD 
Study Monitor: 
PPD 
Amendment 3 Date: 
Amendment 2 Date: 
Amendment 1 Date: 
Original Protocol Date: 
Clinical Operations 
Clmical Operafions, Forty- Seven Inc. 
Telephone: [PPD 
Email: IPPD 
----------
22 December 2018 
14 August 2018 
30 April 2018 
5 February 2018 
Confidentiality statement: 
The concepts and information contained herein are confidential and proprietary and shall 
not be disclosed in whole or part without the express written consent of Forty Seven Inc. 
Compliance Statement: 
This study will be conducted in accordance with this protocol, the International Conference 
on Harmonisation (ICH), Guideline for Good Clinical Practice (GCP), and the applicable 
country and regional (local) regulatory requirements. 
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PROTOCOL APPROVAL PAGE 
I have read the document described above, and my signature below indicates my 
approval: 
PD 
~20/7' 
Date 
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PROTOCOL ACCEPTANCE PAGE 
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), the Declaration of Helsinki, my local and regional clinical trial regulatory 
requirements (including the Code of Federal Regulations [CFR] Title 21 for US 
Investigators), 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: 
 
Name of 
Institution/Site: 
 
Signature: 
 
Date: 
 


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SUMMARY OF CHANGES, AMENDMENT 3 
The main reason for amending the 5F9006 protocol is to remove the requirement 
that patients have received liposomal doxorubicin therapy prior to entering Part 2 
this study. 
The following substantial change has been made to Section 4.1 (Inclusion Criteria): 
• 
Inclusion Criterion 1 for Study Part 2 has been modified to remove the 
requirement that patients have received prior liposomal doxorubicin therapy 
and specify that patients must have documented PD, as determined by 
Gynecologic Cancer lnterGroup (GCIG) Criteria (Rustin 201 1 ), within 
1-6 months after the last day they received the last platinum containing 
chemotherapy. 
Rationale: To simplify the enrollment of a homogeneous group of patients 
with platinum resistant ovarian cancer and allow more patients to potentially 
participate in the study by removing the requirement for prior doxil therapy. 
The following additional changes have been made to the protocol in this 
amendment: 
• 
Specified that T3 (Total) is to be measured (Table 7-1 and Table 7-2) and 
added T3 (Total) and T4 (Free) to the TSH assessment in Table 7-3 and the 
Analyte Listing (Table 7-5). 
Rationale: To accurately specify the tests being performed to measure 
thyroid function. 
• 
Reorganization and consolidation of safety language (Section 9, Assessment 
of Safety, and Table 7-3, Footnote "e"). 
Rationale: To provide more concise content and align language across 
Forty Seven Inc. protocols. 
Editorial changes and updates to style and formatting have been made to improve 
clarity and consistency throughout the document. Changes made in sections of the 
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protocol body have also been made in the protocol synopsis, study design schema, 
tabular schedules of assessments, and elsewhere in the document, as applicable. 


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PROTOCOL SYNOPSIS 
Sponsor:  Forty Seven Inc. 
Investigational Agents:  Hu5F9-G4 in combination with avelumab 
Protocol Number:  5F9006 
Study Title:  A Phase 1b Trial of Hu5F9-G4 in Combination with Avelumab in Solid 
Tumor Patients and Checkpoint-Inhibitor-Naïve Ovarian Cancer Patients Who 
Progress within 6 Months of Prior Platinum Chemotherapy 
Scientific Rationale and Background 
Ovarian cancer is the most frequent cause of gynecologic cancer deaths in the 
United States.  Standard of care for this disease in the frontline and 
platinum-sensitive recurrent setting is platinum-based chemotherapy with or without 
antiangiogenic agents.  More recently, targeted agents such as poly 
adenosine-diphosphate ribose polymerase (PARP) inhibitors have been approved 
by the Food and Drug Administration for women with ovarian cancer (BRCA) 
mutations and/or alterations in the homologous recombination pathway.  Experience 
with newer immunotherapies in this disease, such as the checkpoint inhibitors, has 
not yet matured to impact clinical outcomes.  In women with recurrent ovarian 
cancer, the platinum-free interval (PFI), defined as the interval between the last 
platinum dose and the date of relapse (Rustin 2011), is strongly correlated with the 
likelihood of response to subsequent chemotherapy.  Patients who initially respond 
to systemic therapy with a PFI greater than 1 month, but less than 6 months, have 
been historically referred to as platinum-resistant, and these patients have limited 
treatment options (Davis 2014).  Thus, the development of effective cancer 
treatments for this patient population would address a substantial unmet medical 
need. 
Hu5F9-G4 is a humanized anti-human IgG4 monoclonal antibody (mAb) that binds 
to CD47 and blocks its interaction with its receptor, enabling phagocytosis of human 


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cancer cells (Liu 2015b).  The activity of Hu5F9-G4 is primarily dependent on 
blocking CD47 binding to signal regulatory protein alpha (SIRPα) and not on the 
recruitment of Fc-dependent effector functions, although the presence of the IgG4 
Fc domain is required for its full activity.  For this reason, Hu5F9-G4 was engineered 
with a human IgG4 isotype that is relatively inefficient at recruiting Fc-dependent 
effector functions that might enhance toxic effects on normal CD47 expressing cells 
(Liu 2015b).  Preclinical studies using xenograft cancer models provide compelling 
evidence that Hu5F9-G4 triggers phagocytosis and elimination of cancer cells from 
human solid tumors and hematologic malignancies (Liu 2015b).  Based on this 
mechanism of action (MOA) and its potent preclinical activity, Hu5F9-G4 is being 
developed as a novel therapeutic candidate for solid tumors and hematologic 
malignancies. 
Patients with advanced ovarian cancer who have relapsed or are resistant to 
platinum-based chemotherapy have limited options for effective treatment and an 
overall poor prognosis (Davis 2014).  Consequently, a well-tolerated immunotherapy 
combination that can induce anti-tumor responses and prolong progression-free 
survival (PFS) and overall survival (OS) would be an important therapeutic advance 
in the management of disease in these patients.  Preliminary clinical data from 
Hu5F9-G4 monotherapy in patients with solid tumors suggest that blockade of CD47 
may induce objective responses in heavily pretreated patients with ovarian cancer.  
Furthermore, preclinical studies and our understanding of the mechanism of 
Hu5F9-G4 action suggest that targeting CD47 may generate substantial synergistic 
anti-tumor activity when combined with programmed cell death-ligand 1 (PD-L1) 
checkpoint inhibitors.  Thus, the scientific rationale for exploring the efficacy of this 
combination in this setting is strong. 
Study Objectives and Endpoints 
The study objectives and endpoints are outlined in Synopsis Table 1. 


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Synopsis Table 1:  Study Objectives and Endpoints 
PRIMARY 
 
OBJECTIVES 
ENDPOINTS 
Safety Run-in Cohort: 
To investigate the safety and tolerability of 
Hu5F9-G4 in combination with avelumab in 
patients with advanced solid tumors 
Ovarian Cancer Expansion Cohort: 
To confirm the safety and tolerability of this 
combination and evaluate the anti-tumor 
activity based on Response Evaluation 
Criteria in Solid Tumors (RECIST) v1.1 
(Eisenhauer 2009) in patients with 
checkpoint inhibitor-naïve ovarian cancer, 
fallopian tube cancer, and primary peritoneal 
carcinoma who have previously progressed 
within 1-6 months of receiving platinum 
chemotherapy 
AEs and DLTs graded according to 
National Cancer Institute Common 
Terminology Criteria for Adverse Events 
(NCI CTCAE) Version 4.03 (Appendix C) 
or customized AE severity grading for 
hemagglutination and microangiopathy, 
as defined in Protocol Section 6.5.1.3 
(Safety Management Guidelines) 
Objective response as defined by the 
Investigator according to RECIST v1.1 
(Eisenhauer 2009) 
SECONDARY 
 
OBJECTIVES 
ENDPOINTS 
Safety Run-in Cohort: 
To determine a recommended dose of 
Hu5F9-G4 + avelumab in patients with solid 
tumors 
To examine the pharmacokinetic (PK) profile 
of Hu5F9-G4 in combination with avelumab 
To evaluate the immunogenicity of 
Hu5F9-G4 in combination with avelumab 
Recommended Phase 2 dose and 
schedule (RP2DS) of Hu5F9-G4 in 
combination with avelumab 
Serum concentrations of Hu5F9-G4 
collected at selected time points 
Anti-drug antibodies (ADA) to Hu5F9-G4 
Ovarian Cancer Expansion Cohort: 
To evaluate the anti-tumor activity of 
Hu5F9-G4 in combination with avelumab in 
all patients using the Immune Response 
Evaluation Criteria in Solid Tumors 
(irRECIST; Bohnsack 2014) and, where 
applicable, the Gynecologic Cancer 
Intergroup (GCIG) response criteria 
(Rustin 2011) 
To assess additional efficacy endpoints 
including duration of response (DOR), time 
to tumor progression (TTP), progression-free 
survival (PFS), and overall survival (OS) 
To evaluate the impact of Hu5F9-G4 in 
combination with avelumab on the myeloid 
cell populations in the tumor 
Ovarian Cancer Expansion Cohort: 
Objective response, as defined by the 
Investigator according to irRECIST 
(Bohnsack 2014) and GCIG response 
criteria (Rustin 2011) 
For patients who respond, DOR will be 
evaluated.  For all patients, efficacy 
endpoints will include TTP, PFS, and OS. 
Immunohistochemical staining of myeloid 
cells in formalin-fixed, paraffin-embedded 
tissues 


Hu5F9-G4 
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microenvironment, as assessed in 
sequential tumor biopsies in patients with 
platinum-resistant ovarian cancer 
Overall Study Design: 
Page 9 of 160 
This is an open label, multicenter, Phase 1 b trial investigating the combination of 
Hu5F9-G4 and avelumab in patients with solid tumors and checkpoint inhibitor-na'iVe 
ovarian cancer who progressed within 1-6 months of receiving platinum-containing 
chemotherapy. Checkpoint inhibitor-na'iVe patients are defined as those patients 
who have not been previously treated with an anti-PD-1 , anti-PD-L 1, anti-PD-L2, 
anti-CD137, or anti-CTLA-4 antibody (including ipilimumab, tremelimumab, or any 
other antibody or drug specifically targeting T-cell co-regulatory proteins). 
in Part 2, mandatory 
pretreatment and during-treatment biopsies will be collected as described in Protocol 
Section 7.3.11. 
The study will be conducted in 2 parts: Part 1 (Dose Evaluation/Safety Run-in) and 
Part 2 (Expansion in Ovarian Cancer), as follows: 
Part 1 - Dose Evaluation/Safety Run-in 
Patients with solid tumors will be treated at the starting dose with Hu5F9-G4 + 
avelumab to examine the safety and pharmacokinetics (PK) of this study drug 
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combination.  The Safety Run-in Cohort will begin by treating 6 patients, up to a total 
of 12 patients evaluable for dose-limiting toxicity (DLT). 
The dose levels and schedules for both study drugs are described in 
Synopsis Table 2.  Dose evaluation decisions will be made by the Clinical Trial 
Steering Committee (CTSC), and DLTs for the combination regimen will be 
monitored from administration of the priming dose on Day 1 to the end of Cycle 1 
(Day 35).  The first patient in each dose level cohort will be treated for 14 days prior 
to enrolling additional patients.  After the first 6 patients evaluable for DLT 
assessment have safely completed the Cycle 1 DLT evaluation period, and if no 
more than 1 DLT occurs, the cohort will be deemed to be safe by the CTSC 
(Protocol Section 11.3) (Synopsis Table 2).  The recommended dose for patients in 
the Expansion Cohort must have a DLT rate less than 33% in at least 6 evaluable 
patients, and the final dose selection for Part 2 will be made by the CTSC after all 
available clinical, 
and PK data are reviewed.  Up to an additional 
6 evaluable patients may be enrolled in any cohort to further evaluate safety and PK. 
The first cycle will be 5 weeks in duration; subsequent cycles will last 4 weeks.  
Initial tumor response assessments will be performed at Cycle 3 and then after every 
8 weeks of treatment (every 2 cycles).  
 
 
Dose-Limiting Toxicity Definition 
A DLT is defined as any Grade 3 or greater adverse event (AE) that is assessed as 
related to at least 1 study drug that occurs during the 5-week DLT Assessment 
Period, defined as the first 5 weeks of treatment for each patient. Additionally, any 
treatment-emergent adverse event (TEAE) that is, in the opinion of the CTSC, of 
potential clinical significance such that further dosing would expose patients to 
unacceptable risk, will be considered a DLT. Exceptions to the DLT definition are 
outlined in Protocol Section 3.2.1.2. DLT assessment is outlined in Protocol 
Section 3.2.1. 
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Synopsis Table 2:  Part 1 Hu5F9-G4 and Avelumab Dose Levels and Schedule 
Dose 
Cohort 
Drug/Dose 
(Intravenous) 
Dose Schedule 
Cycle 1 
(35 days) 
Cycle 2 
(28 days) 
Cycle 3+ 
(28 days) 
1 
Hu5F9-G4 — 1 mg/kg (priming 
dose) 
Over 3 hours (± 30 minutes) 
Infusion should begin at least 
1 hour after completion of the 
avelumab infusion (on days when 
both are administered) 
Day 1 
— 
— 
Hu5F9-G4 — 30 mg/kg  
Over 2 hours (± 30 minutes)  
Infusion should begin at least 
1 hour after completion of the 
avelumab infusion (on days when 
both are administered) 
Days 8, 15, 
22, 29 
Days 1 and 15 
Days 1 and 15 
Avelumab — 800 mg Q2W 
Over 1 hour (-10 to +20 minutes)  
Days 8 and 22 
Days 1 and 15 
Days 1 and 15 
2 
Hu5F9-G4 — 1 mg/kg (priming 
dose) 
Over 3 hours (± 30 minutes) 
Infusion should begin at least 
1 hour after completion of the 
avelumab infusion (on days when 
both are administered) 
Day 1 
— 
— 
Hu5F9-G4 — 45 mg/kg  
Over 2 hours (± 30 minutes)  
Infusion should begin at least 
1 hour after completion of the 
avelumab infusion (on days when 
both are administered) 
Days 8, 11, 
15, 22, 29 
Days 1, 8, 15, 
22 
Days 1 and 15 
Avelumab — 800 mg Q2W 
Over 1 hour (-10 to +20 minutes)  
Days 8 and 22 
Days 1 and 15 
Days 1 and 15 
The following lower dose cohort may be used if ≥2 of 6 patients in Dose Level 1 
experience DLTs: 
-1 
Hu5F9-G4 — 1 mg/kg (priming 
dose) 
Over 3 hours (± 30 minutes) 
Infusion should begin at least 
1 hour after completion of the 
avelumab infusion (on days when 
both are administered) 
Day 1 
— 
— 


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Dose 
Cohort 
Drug/Dose 
(Intravenous) 
Dose Schedule 
Cycle 1 
(35 days) 
Cycle 2 
(28 days) 
Cycle 3+ 
(28 days) 
Hu5F9-G4 — 20 mg/kg a 
Over 2 hours (± 30 minutes)  
Infusion should begin at least 
1 hour after completion of the 
avelumab infusion (on days when 
both are administered) 
Days 8, 15, 
22, 29 
Days 1 and 15 
Days 1 and 15 
Avelumab — 800 mg Q2W 
Over 1 hour (-10 to +20 minutes)  
Days 8 and 22 
Days 1 and 15 
Days 1 and 15 
The following lower dose cohort may be used if ≥2 of 6 patients in Dose Level 2 
experience DLTs: 
 
Hu5F9-G4 — 1 mg/kg (priming 
dose) 
Over 3 hours (± 30 minutes) 
Infusion should begin at least 
1 hour after completion of the 
avelumab infusion (on days when 
both are administered) 
Day 1 
— 
— 
-2 
Hu5F9-G4 — 30 mg/kg a 
Over 2 hours (± 30 minutes) 
Infusion should begin at least 
1 hour after completion of the 
avelumab infusion (on days when 
both are administered) 
Days 8, 11, 
15, 22, 29 
Days 1, 8, 15, 
22 
Days 1 and 15 
 
Avelumab — 800 mg Q2W 
Over 1 hour (-10 to +20 minutes)  
Days 8 and 22 
Days 1 and 15 
Days 1 and 15 
Abbreviations:  DLT = dose-limiting toxicity; Q2W = once every 2 weeks. 
a. If additional dose reductions are required but the patient is deemed to be benefitting from 
treatment, the dose of Hu5F9-G4 may be reduced by an additional 50%. 
 
Part 2 - Expansion in Ovarian Cancer: 
Checkpoint inhibitor-naïve ovarian cancer patients will be treated with Hu5F9-G4 + 
avelumab to evaluate the safety, efficacy, 
 
effects of this study drug combination. 
Once the Part 1 Safety Run-in Cohort of the trial is completed and the recommended 
expansion dose(s) is determined, the CTSC will open Part 2 of the study.  Part 2 of 
the study will treat up to 20 patients with ovarian cancer at the recommended 
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dose(s) to confirm safety, PK, 
and to document preliminary 
efficacy in this population. 
In Part 2, patients may be enrolled simultaneously without an observation period 
after the first patient starts treatment.  Based on review of ongoing dosing data, the 
CTSC may recommend testing of multiple doses in Phase 2 and each dose level 
tested will enroll a total of 20 patients.  In Part 2, mandatory tumor biopsies will be 
collected, where medically feasible, from all patients during the Screening Period 
prior to first dose and at Cycle 3, Day 1 (± 2 weeks).  
 
Efficacy will be evaluated using Response 
Evaluation Criteria in Solid Tumors (RECIST v1.1; primary endpoint; Eisenhauer 
2009) and Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST; 
secondary endpoint; Bohnsack 2014).  Study treatment may be continued until an 
unacceptable drug-related toxicity occurs or until disease progression according to 
irRECIST. 
Clinical Trial Steering Committee (CTSC) 
The CTSC will oversee the conduct of the clinical trial.  A representative from the 
Sponsor, usually the Study Medical Monitor or designee, will chair the CTSC.  
The CTSC will have representation from each participating site in the study.  
The CTSC will review safety and efficacy data generated during the trial and make 
decisions about patient recruitment, trial management, initiation of protocol specific 
amendments, expansion of cohorts, using higher or lower dose levels, defining any 
new dose cohorts, identification of the recommended dose for Part 2 
 
.  The CTSC will meet at a minimum at the completion of the DLT period for 
each cohort in the Safety Run-in part of the trial, at any protocol-specified formal 
interim analyses, and when emergent critical safety data are reported.  
The composition, structure, and function of the CTSC are defined in the 
CTSC Charter. 
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Duration of Treatment 
Patients may continue treatment unless they develop unacceptable toxicities that 
cannot be clinically managed by dose or schedule modifications as outlined in 
Protocol Section 6.4, or if they have confirmed progressive disease (PD) according 
to irRECIST, as described in Protocol Section 10.1.  Hu5F9-G4 and avelumab 
combination treatment may continue past the initial determination of disease 
progression according to irRECIST as long as the following criteria are met: 
• No new symptoms or worsening of previous symptoms 
• Tolerance of Hu5F9-G4 and avelumab 
• Stable Eastern Cooperative Oncology Group (ECOG) performance status 
• Treatment beyond progression will not delay an imminent intervention to 
prevent serious complications of disease progression (for example, central 
nervous system metastases) 
The decision to continue treatment should be discussed with the Medical Monitor 
and documented in the trial records. 
Overview of Assessments 
Assessments will be performed according to the schedules provided in Protocol 
Section 7 (Table 7-1, Table 7-2, Table 7-3, and Table 7-4). 
Safety assessments include vital signs, physical exam, electrocardiograms, ECOG 
performance status score, pregnancy testing (for female patients), AEs, laboratory 
tests (hematology, serum chemistries, urinalysis, and coagulation), monitoring of 
concomitant medications, and incidence of anti-drug (ADA) antibodies. 
Appropriate cancer staging assessments should be performed.  Response 
assessments will be by imaging to be conducted according to RECIST v1.1 and 
irRECIST as described in Protocol Section 10.1.  The same imaging modality used 
at Screening should be used throughout the study whenever possible. 
The first response assessment will occur at Cycle 3, Day 1 (±1 week).  After Cycle 3, 
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will occur every 2 cycles.  Response assessment will be obtained at treatment 
termination, unless a prior radiographic assessment was performed within the past 
4 weeks or a prior response assessment showed documented confirmed PD. 
Tumor markers should be obtained at Screening (Section 7.3.11).  If applicable, they 
should be obtained on Day 1 of Cycles 2, 3, and 4.  From Cycle 5 and onward, they 
may be obtained every 2 cycles. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
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Planned Number of Patients 
The Safety Run-in Cohort (Part 1) will begin by treating 6 patients and will enroll up 
to 18 patients evaluable for DLT. 
The Ovarian Cancer Expansion Cohort (Part 2) will treat up to 20 patients with 
ovarian cancer at the recommended dose to confirm safety, PK, 
 
and to document preliminary efficacy in this population.  Each dose level tested in 
Phase 2 will enroll a total of 20 patients. 
Inclusion Criteria (All Patients) 
1. Meets the criteria for the appropriate cohort: 
• Part 1 Safety Run-in Cohort:  Pathologically confirmed advanced solid 
tumors for which no further conventional therapy is suitable for the 
patient and for which there is no curative therapy available.  Prior 
checkpoint inhibitor treatment therapy is permitted. 
• Part 2 Ovarian Cancer Expansion Cohort:  Histologically or 
cytologically confirmed, epithelial ovarian, fallopian tube, or peritoneal 
cancer patients who are checkpoint inhibitor-naïve.  All histological 
subtypes of ovarian epithelial tumors are allowed.  Patients must have 
had, at any point, documented PD as determined by Gynecologic 
Cancer InterGroup (GCIG) criteria (Rustin 2011) within 1-6 months 
after the last day of receiving the last platinum-containing 
chemotherapy.  Patients must have received at least 1 prior line of a 
platinum-based chemotherapy regimen to be eligible.  Patients may 
have received any additional number of prior systemic therapies for 
metastatic disease including PARP inhibitors. 
2. Part 2 Ovarian Cancer Expansion Cohort:  Disease must be measurable or 
assessable for response according to RECIST v1.1 (primary endpoint) and 
irRECIST (secondary endpoint). 
3. Age ≥18 years. 
4. ECOG Performance Status 0 to 2 (Appendix D). 
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5. Laboratory measurements, blood counts: 
• Hemoglobin ≥9.5 g/dL (red blood cell [RBC] transfusions are permitted 
during the Screening Period and prior to enrollment to meet the 
hemoglobin inclusion criterion.) 
• Absolute neutrophil count (ANC) ≥1.5 × 109/L. 
• Platelets ≥100 × 109/L. 
6. Laboratory measurements, hepatic function: 
• Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) 
≤3 × upper limit of normal (ULN), or ≤5 × ULN for patients with 
intrahepatic liver metastases. 
• Bilirubin ≤1.5 × ULN or ≤3.0 × ULN and primarily unconjugated if 
patient has a documented history of Gilbert’s syndrome or a genetic 
equivalent. 
7. Laboratory measurements, renal function: 
• Serum creatinine ≤1.5× ULN or if elevated, a calculated glomerular 
filtration rate (GFR) >30 mL/min/1.73 m2. 
8. For patients in Part 1 
 
 a formalin-fixed paraffin-embedded (FFPE) block 
containing tumor tissue not older than 6 months from the time of screening or 
a minimum of 10 (preferably 25) unstained tumor slides (cut within 1 week) 
suitable for PD-L1 expression assessment will be collected.  The tissue 
should be collected from a non-irradiated area and there should be at least 
1 measurable lesion remaining for tumor response assessment. 
9. Negative urine or serum pregnancy test within 30 days before enrollment and 
within 72 hours before the first administration of study drug for female patients 
of childbearing potential. 
10. Female patients of childbearing potential must be willing to use 1 highly 
effective method of contraception during the study and continue for 4 months 
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after the last dose of Hu5F9-G4 and 1 month after the last dose of avelumab 
(Protocol Section 4.6.1). 
11. Male patients who are sexually active with a woman of childbearing potential 
and who have not had vasectomies must be willing to use a highly effective 
barrier method of contraception during the study and for 4 months after the 
last dose of Hu5F9-G4 and 1 month after the last dose of avelumab 
(Protocol Section 4.6.2). 
12. Patient has provided informed consent. 
13. Must be willing and able to comply with the clinic visits and procedures 
outlined in the study protocol. 
14. For Part 2 (Ovarian Cancer Expansion Cohort) only:  Willing to consent to 
1 mandatory pre-treatment and 1 during-treatment tumor biopsy unless not 
medically feasible as determined by the Investigator (reasons include, but are 
not limited to, lack of accessible tumor tissue to biopsy and patient safety 
issues). 
Exclusion Criteria 
1. Patients with symptomatic or untreated central nervous system (CNS) 
metastases.  (Patients with stable, asymptomatic, treated CNS lesions, who 
are off of corticosteroids and radiation therapy for at least 3 weeks are 
permitted.) 
2. Prior or concurrent anti-cancer therapy including chemotherapy, hormonal 
therapy, or investigational agents within 2 weeks or within at least 4 half-lives 
prior to Hu5F9-G4 dosing (up to a maximum of 4 weeks), whichever is longer.  
In all situations, the maximum required washout period will not exceed 
4 weeks prior to the day of first treatment with Hu5F9-G4. 
The following are not criteria for exclusion: 
• Localized non-CNS radiotherapy (>14 days before enrollment) 
• Previous hormonal therapy with luteinizing-hormone releasing 
hormone (LHRH) agonists for prostate cancer 


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• Low dose steroids (oral prednisone or equivalent ≤10 mg per day) 
• Treatment with bisphosphonates and receptor activator of nuclear 
factor kappa-B ligand (RANKL) inhibitors 
3. For Part 2 Ovarian Cancer Expansion Cohort only:  Prior therapy with an 
anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody 
(including ipilimumab, tremelimumab, or any other antibody or drug 
specifically targeting T-cell co-regulatory proteins). 
4. Prior treatment with CD47 or SIRPα targeting agents. 
5. Known active or chronic hepatitis B or C infection or human 
immunodeficiency virus (HIV). 
6. RBC transfusion dependence, defined as requiring more than 2 units of RBCs 
transfused during the 4-week period prior to Screening.  RBC transfusions are 
permitted during the Screening Period and prior to enrollment to meet the 
hemoglobin inclusion criteria. 
7. Prior organ transplantation, including allogeneic stem-cell transplantation, 
requiring immunosuppression. 
8. Prior hemolytic anemia or Evans Syndrome in the last 3 months. 
9. Hypersensitivity to the active substance or to any of the other excipients of 
Hu5F9-G4 or avelumab, including known severe hypersensitivity reactions to 
monoclonal antibodies (NCI CTCAE v4.03, Grade ≥3; Appendix C). 
10. Significant medical diseases or conditions that would substantially worsen the 
risk-benefit ratio of participating in the study.  This includes, but is not limited 
to, acute myocardial infarction within the last 6 months, unstable angina, 
significant acute or chronic infections, severely immunocompromised state, 
and congestive heart failure (New York Heart Association [NYHA] Class II-IV). 
11. Known history of inflammatory colitis, inflammatory bowel disease, 
pneumonitis, or pulmonary fibrosis. 
12. History of uncontrolled intercurrent illness including but not limited to: 


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• Hypertension uncontrolled by standard therapies (not stabilized to 
150/90 mmHg or lower) 
• Uncontrolled active infection 
• Uncontrolled diabetes (e.g., hemoglobin A1c ≥8%) 
• Uncontrolled asthma 
13. Radiotherapy within 14 days prior to enrollment. 
14. For Part 2 Expansion Cohort only:  Previous malignant disease (other than 
the tumor disease for this trial and with the exception of adequately treated 
non-melanoma skin cancers, and carcinoma in situ of skin, bladder, cervix, 
colon/rectum, or breast) unless in a stable remission for at least 2 years prior 
to study entry. 
15. History of psychiatric illness or substance abuse likely to interfere with ability 
to comply with protocol requirements or give informed consent. 
16. Patient or designees are or become incapable of providing legal informed 
consent. 
17. Current use of the following medications at the time of enrollment: 
• Immunotherapy or immunosuppressive drugs (e.g., chemotherapy or 
systemic corticosteroids) EXCEPT for the following:  a. intranasal, 
inhaled, topical steroids, or local steroid injection (e.g., intra-articular 
injection); b. systemic corticosteroids at physiologic doses ≤10 mg/day 
of prednisone or equivalent; c. steroids as premedication for 
hypersensitivity reactions (e.g., CT scan premedication). 
• Growth factors (granulocyte colony stimulating factor or granulocyte 
macrophage colony stimulating factor) EXCEPT for erythropoietin and 
darbepoetin alpha. 
• Herbal remedies with immunostimulating properties (e.g., mistletoe 
extract) or known to potentially interfere with major organ function 
(e.g., hypericin). 
18. Administration of a live vaccine within 28 days prior to enrollment. 


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19. Pregnancy or active breast feeding. 
20. Active autoimmune disease or treatment with systemic immunosuppression 
for organ transplantation. 
The following are not criteria for exclusion: 
• Type I diabetes mellitus 
• Vitiligo 
• Mild-to-moderate psoriasis 
• Clinically stable hypo- or hyperthyroid disease not requiring 
immunosuppressive treatment 
21. Positive IgG component of the direct antiglobulin test (DAT). 
Test Product, Dose, and Mode of Administration 
Hu5F9-G4 is a humanized IgG4 monoclonal antibody of the IgG4 kappa isotype 
containing a Ser-Pro (S-P) substitution in the hinge region (position 228) of the 
heavy chain to reduce Fab arm exchange.  Hu5F9-G4 is a humanized monoclonal 
antibody against CD47 which is administered intravenously (IV). 
Part 1 Dose:  The precise starting dose for Hu5F9-G4 will be a priming dose of 
1 mg/kg in Week 1 followed by 30 mg/kg weekly for 4 doses.  Starting in Cycle 2, 
30 mg/kg of Hu5F9-G4 will be given every 2 weeks.  This Hu5F9-G4 dose will be 
combined with the full single-agent dose of 800 mg of avelumab given once every 
2 weeks (Synopsis Table 2).  Other doses and schedules may be tested as 
described above in Part 1:  Dose Evaluation/Safety Run-in. 
Part 2 Dose:  Once the Part 1 Safety Run-in Cohort of the trial is completed and the 
recommended expansion dose(s) is determined, the CTSC will open Part 2 of the 
study.  Part 2 of the study will treat up to 20 patients with ovarian cancer at the 
recommended dose(s) to confirm safety, PK, 
and to document 
preliminary efficacy in this population.  Each dose level tested in Phase 2 will enroll 
20 patients. 
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Combination Therapy, Dose, and Mode of Administration 
Avelumab (BAVENCIO®) is a programmed death ligand-1 (PD-L1) blocking 
antibody.  Avelumab is a human IgG1 lambda monoclonal antibody that has a 
molecular weight of approximately 147 kDa. 
Part 1 Dose:  Avelumab will be administered IV at a fixed dose of 800 mg over 
1 hour (˗10 to +20 minutes) (Synopsis Table 2).  Because of the different cycle 
lengths (due to the priming dose of Hu5F9-G4) Cycle 1 doses will be administered 
on Days 8 and 22, while doses in Cycles 2+ will be administered on Days 1 and 15.  
Drugs should not be co-administered through the same IV line. 
Part 2 Dose:  Avelumab will be dosed based on the final dose selection that will be 
made by the CTSC after all available clinical, 
 and PK data are 
reviewed from Part 1. 
On days when both study drugs are given, Hu5F9-G4 will be administered at least 
1–2 hours after the completion of the avelumab infusion. 
Study Endpoints 
The study objectives and endpoints are outlined above in Synopsis Table 1. 
Statistical Methods and Analyses 
Safety:  The statistical analysis will be descriptive, providing listings, graphical 
displays, frequencies, and percentages for discrete variables and/or the mean, 
standard deviation, median, and ranges for continuous variables.  Safety 
variables to be examined include DLTs for patients in Part 1, TEAEs (AEs 
worsening or occurring during or after a patient’s first exposure to study drug), 
study drug-related adverse events, vital signs, physical examinations, laboratory, 
and ADA assessments.  AEs will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA, Version 19.0) and grouped by system organ 
class and preferred term.  Summary tables will include the number and 
percentage of patients with AEs, serious adverse events (SAEs), fatal AEs, and 
other AEs of interest. 
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Data will be presented by Part 1 (Safety Run-in Cohort) and by Part 2 (Ovarian 
Cancer Expansion Cohort), and, where relevant, summarized across various 
dose cohorts. 
Efficacy:  The efficacy analyses will include analysis of the outcome measures of 
overall response rate (ORR) using RECIST and irRECIST, duration of response 
(DOR), time to progression (TTP), progression-free survival (PFS), and overall 
survival (OS).  ORR will be summarized by frequency and percentages along 
with 95% exact confidence interval.  The time-to-event endpoints of DOR, TTP, 
PFS, and OS will be summarized using Kaplan-Meier methods.  Additional 
details will be provided in the Statistical Analysis Plan (SAP). 
Pharmacokinetics:  Based on the distinct MOAs of Hu5F9-G4 and avelumab, 
drug-drug PK interactions are not expected.  Thus, samples for PK analysis for 
avelumab will be biobanked and will be analyzed based on CTSC 
recommendation.  Summaries of PK concentration data and PK parameters will 
be provided.  Due to the sparse sampling regime, it is anticipated that the 
maximum serum concentration (Cmax) after the first dose will be the only 
calculable PK parameter in this population. 
Immunogenicity Analyses:  The rate and magnitude of anti-Hu5F9-G4 antibody 
positivity will be evaluated for all patients in Parts 1 and 2 of the trial, and for the 
pooled patient population.  
 
 
 
  Immunogenicity analysis may also be performed for avelumab.  
However, it is not expected that Hu5F9-G4 will impact the immunogenicity of 
avelumab and vice versa. 
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Sample Size Determination: 
This trial will include a total of up to 40 patients.  This sample size includes both 
Parts 1 and 2 of the study, allowing for patient replacement as defined in this 
protocol.  In Part 1, up to 12 -18 patients will be treated in a Safety Run-in Cohort, 
assuming that no more than 2 DLTs in each cohort of 6 patients occur.  Up to 
18 patients may be enrolled in Part 1 if some patients are ineligible for DLT 
assessment. 
Part 2 consists of a single expansion cohort in 20 ovarian cancer patients who will 
undergo safety, PK, 
.  Each dose level tested in 
Part 2 will enroll 20 patients.  This sample size will allow for confirmation of the 
safety profile of Hu5F9-G4 and avelumab in this population, and the mandatory 
tumor biopsies 
.  The anti-tumor 
activity of this regimen will also be documented.  With this sample size, the lower 
bound of the 95% exact confidence interval would exclude 10% if the objective 
response rate is 30% or higher.
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STUDY DESIGN SCHEMA, PART 1 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
  
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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STUDY DESIGN SCHEMA, PART 2 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
    
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
PROTOCOL APPROVAL PAGE ............................................................................... 2 
PROTOCOL ACCEPTANCE PAGE .......................................................................... 3 
SUMMARY OF CHANGES, AMENDMENT 3 ............................................................ 4 
PROTOCOL SYNOPSIS ............................................................................................ 6 
STUDY DESIGN SCHEMA, PART 1 ....................................................................... 25 
STUDY DESIGN SCHEMA, PART 2 ....................................................................... 26 
TABLE OF CONTENTS ........................................................................................... 27 
ABBREVIATIONS AND DEFINITIONS ................................................................... 32 
1. BACKGROUND ................................................................................................ 36 
1.1. Ovarian Cancer ..................................................................................... 36 
1.2. Study Drug:  Hu5F9-G4, a CD47-Blocking Antibody ............................. 36 
1.2.1. 
CD47 Biology ........................................................................... 36 
1.2.2. 
Hu5F9-G4 ................................................................................ 39 
1.2.3. 
Preclinical Studies .................................................................... 39 
1.2.4. 
Hu5F9-G4 Clinical Studies ....................................................... 40 
1.3. Preclinical Combination Studies ............................................................ 46 
1.4. Translational Studies Background ........................................................ 47 
1.5. Avelumab .............................................................................................. 49 
1.6. Starting Dose Rationale ........................................................................ 51 
1.6.1. 
Hu5F9-G4 Dose ....................................................................... 51 
1.6.2. 
Avelumab Dose ........................................................................ 53 
1.7. Study Rationale and Risk-Benefit ......................................................... 54 
2. STUDY OBJECTIVES AND ENDPOINTS ........................................................ 55 
3. STUDY DESIGN ................................................................................................ 57 
3.1. Overall Study Design ............................................................................ 57 
3.2. Part 1 Safety Run-in Cohort:  Study Design .......................................... 59 
3.2.1. 
Dose-Limiting Toxicity Assessment .......................................... 62 
3.3. Part 2 Expansion:  Study Design .......................................................... 64 
3.4. Number of Sites .................................................................................... 65 
3.5. Estimated Study Duration ..................................................................... 65 
4. PATIENT SELECTION AND ENROLLMENT ................................................... 66 
4.1. Inclusion Criteria ................................................................................... 66 
4.2. Exclusion Criteria .................................................................................. 69 
4.3. Patient Screening .................................................................................. 71 
4.4. Informed Consent Process.................................................................... 72 
4.5. Registration Process ............................................................................. 72 


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4.6. Contraception Requirements ................................................................ 73 
4.6.1. 
Female Patients ....................................................................... 73 
4.6.2. 
Male Patients ........................................................................... 74 
5. STUDY DRUG INFORMATION ......................................................................... 74 
5.1. Physical Description of Study Drug ....................................................... 74 
5.1.1. 
Hu5F9-G4 ................................................................................ 74 
5.1.2. 
Avelumab ................................................................................. 75 
6. TREATMENT ADMINISTRATION ..................................................................... 75 
6.1. Study Drug Administration Guidance:  Hu5F9-G4 and Avelumab ......... 75 
6.1.1. 
Dosing ...................................................................................... 75 
6.1.2. 
Premedication .......................................................................... 76 
6.1.3. 
Timing of Dosing ...................................................................... 77 
6.1.4. 
Patient Monitoring After Infusion .............................................. 77 
6.1.5. 
Repriming ................................................................................. 77 
6.2. Hu5F9-G4 Preparation and Administration ........................................... 78 
6.2.1. 
Preparation .............................................................................. 78 
6.2.2. 
Administration .......................................................................... 79 
6.3. Avelumab Preparation and Administration ............................................ 80 
6.3.1. 
Preparation .............................................................................. 80 
6.3.2. 
Administration .......................................................................... 80 
6.4. Dose Delays, Dose Modifications, and Treatment Termination ............ 81 
6.4.1. 
Treatment Termination:  Hu5F9-G4 and Avelumab ................. 81 
6.4.2. 
Hu5F9-G4 ................................................................................ 81 
6.4.3. 
Avelumab ................................................................................. 85 
6.5. Safety Management Guidelines ............................................................ 86 
6.5.1. 
Hu5F9-G4-related Events ........................................................ 86 
6.5.2. 
Avelumab-related Events ......................................................... 91 
6.6. Prohibited Medications .......................................................................... 99 
6.6.1. 
Hu5F9-G4 ................................................................................ 99 
6.6.2. 
Avelumab ............................................................................... 100 
6.7. Post-therapy Follow-up and Patient Study Completion ....................... 101 
7. STUDY EVALUATIONS .................................................................................. 102 
7.1. Schedules of Assessment for Part 1 and Part 2.................................. 102 
7.2. Screening Assessments ..................................................................... 114 
7.3. Study Procedures ............................................................................... 114 
7.3.1. 
Physical Examination ............................................................. 114 
7.3.2. 
Vital Signs .............................................................................. 115 
7.3.3. 
Electrocardiograms ................................................................ 115 


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7.3.4. 
Eastern Cooperative Oncology Group Performance Status ... 115 
7.3.5. 
Pregnancy Test ...................................................................... 115 
7.3.6. 
Laboratory Tests .................................................................... 116 
7.3.7. 
Urinalysis ............................................................................... 120 
7.3.8. 
Pharmacokinetic Assessments .............................................. 120 
7.3.9. 
Pharmacodynamic and Biomarker Assessments ................... 121 
7.3.10. Anti-drug Antibodies ............................................................... 121 
7.3.11. Tumor Biopsies ...................................................................... 122 
7.3.12. Response Assessments ......................................................... 122 
7.3.13. Adverse Events ...................................................................... 123 
7.3.14. Concomitant Medications ....................................................... 123 
7.3.15. End of Treatment Visit ............................................................ 124 
7.3.16. Safety Follow-up .................................................................... 124 
7.3.17. Long-term Follow-up .............................................................. 124 
7.3.18. Survival Follow-up .................................................................. 125 
8. STUDY DISCONTINUATION .......................................................................... 125 
8.1. Withdrawal of Patients from Study Drug Treatment ............................ 125 
8.2. Withdrawal of Patients from Study ...................................................... 126 
8.3. Defining the End of Study ................................................................... 127 
8.4. Study Termination ............................................................................... 127 
9. ASSESSMENT OF SAFETY ........................................................................... 128 
9.1. Safety Parameters and Definitions ...................................................... 128 
9.1.1. 
Adverse Event ........................................................................ 128 
9.1.2. 
Serious Adverse Event ........................................................... 129 
9.2. Methods and Timing for Capturing and Assessing Safety 
Parameters ....................................................................................... 130 
9.2.1. 
Adverse Event Reporting Period ............................................ 130 
9.2.2. 
Eliciting Adverse Events ......................................................... 131 
9.2.3. 
Assessment of Severity and Causality of Adverse Events ..... 131 
9.3. Procedures for Recording Adverse Events ......................................... 133 
9.3.1. 
Recording Adverse Events ..................................................... 133 
9.4. Reporting Requirements for Serious Adverse Events ......................... 137 
10. MEASUREMENT OF EFFECT ........................................................................ 138 
10.1. Anti-Cancer Effect ............................................................................... 138 
11. STATISTICAL CONSIDERATIONS ................................................................ 138 
11.1. Analysis Sets ...................................................................................... 139 
11.1.1. Part 1 Safety Run-In Cohort ................................................... 139 
11.1.2. Parts 1 and 2 Safety and Efficacy Analysis Cohort ................ 139 


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11.2. Sample Size Determination................................................................. 140 
11.3. Clinical Trial Steering Committee ........................................................ 140 
11.4. Data Monitoring Committee ................................................................ 141 
11.5. Analysis of the Conduct of the Study .................................................. 141 
11.6. Statistical Methods .............................................................................. 141 
11.6.1. Efficacy Analyses ................................................................... 141 
11.6.2. Safety Analyses ..................................................................... 142 
11.6.3. Pharmacokinetic Analyses ..................................................... 143 
 
11.6.5. Immunogenicity Analyses ...................................................... 144 
11.7. Handling of Missing Data .................................................................... 145 
12. ETHICAL AND ADMINISTRATIVE CONSIDERATIONS ................................ 145 
12.1. Compliance Statement ........................................................................ 145 
12.2. Investigator Responsibilities ................................................................ 145 
12.3. Institutional Review Board or Independent Ethics Committee............. 146 
12.4. Informed Consent and Human Subject Protection .............................. 147 
12.5. Confidentiality ..................................................................................... 148 
12.6. Urgent Safety Measures ..................................................................... 149 
12.7. Serious Breaches and Fraud .............................................................. 149 
12.8. Study Monitoring ................................................................................. 150 
12.9. Audits and Inspections ........................................................................ 150 
12.10. Data Collection and Handling ........................................................... 150 
12.11. Maintenance of Source Documents and Record Retention .............. 152 
 
12.13. Financing and Insurance................................................................... 154 
12.14. Publication Policy .............................................................................. 154 
13. REFERENCES ................................................................................................ 155 
14. APPENDICES ................................................................................................. 158 
Appendix A.  Avelumab Study Information for JAVELIN 100 ....................... 158 
Appendix B.  Avelumab Prescribing Information .......................................... 158 
Appendix C.  National Cancer Institute Common Terminology Criteria for 
Adverse Events ................................................................................. 158 
Appendix D.  Eastern Cooperative Oncology Group Performance Status ... 159 
Appendix E.  Peripheral Smear Assessment ............................................... 160 
 
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LIST OF TABLES 
Table 2-1. 
Objectives and Endpoints ............................................................... 55 
Table 3-1. 
Part 1 Hu5F9-G4 and Avelumab Dose Levels and Schedule ......... 61 
Table 6-1. 
Hu5F9-G4-related Toxicities Requiring Dose Reduction ................ 82 
Table 6-2. 
Treatment Modification for Symptoms of Infusion-related 
Reactions Associated with Avelumab ............................................. 92 
Table 6-3. 
Management of Immune-Related Adverse Events (Avelumab) ...... 93 
Table 7-1. 
Schedule of Assessments (Study Part 1 and Part 2, Dose 
Level 1) ......................................................................................... 103 
Table 7-2. 
Schedule of Assessments (Study Part 1 and Part 2, Dose 
Level 2) ......................................................................................... 107 
Table 7-3. 
Schedule of Assessments for Follow-up (Study Part 1 and 
Part 2, All Dose Levels) ................................................................ 111 
Table 7-4. 
Blood Sampling Times for PK 
 (Study 
Part 1 and Part 2) ......................................................................... 113 
Table 7-5. 
Analyte Listing .............................................................................. 117 
Table 9-1. 
Adverse Event Grade (Severity) Scale ......................................... 132 
Table 9-2. 
Causal Attribution Guidance ......................................................... 133 
Table 14-1. 
Eastern Cooperative Oncology Group Performance Status ......... 159 
LIST OF FIGURES 
Figure 1-1. 
CD47 mRNA Expression Levels May be a Prognostic Factor ........ 38 
Figure 1-2. 
Anti-CD47 Antibody Therapy Eliminates Ovarian Cancer 
Cells In Vivo and Cures Mice Xenografted with Patient 
Ovarian Cancer .............................................................................. 40 
Figure 1-3. 
Avelumab but Not Other Checkpoint Inhibitor Antibodies 
Enhance Phagocytosis of Cancer Cells in Combination with 
Hu5F9-G4 ....................................................................................... 47 
 
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ABBREVIATIONS AND DEFINITIONS 
ABO 
any of the four blood groups A, B, AB, and O comprising the ABO system 
ADA 
anti-drug antibodies 
ADL 
activities of daily life 
AE 
adverse event 
AHA 
American Heart Association 
ALL 
acute lymphoblastic leukemia 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
API 
active pharmaceutical ingredient 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
BOR 
best overall response 
BRCA 
breast cancer susceptibility gene 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CI 
confidence interval 
CFR 
Code of Federal Regulations 
Cmax 
maximum concentration 
CMV 
cytomegalovirus 
CNS 
central nervous system 
CR 
complete response 
CRC 
colorectal cancer 
CRO 
clinical research organization 
CT 
computed tomography 
CTLA-4 
cytotoxic T-lymphocyte-associated antigen 4 
CTSC 
Clinical Trial Steering Committee 
DAT 
direct antiglobulin test 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
EAS 
Efficacy Analysis Set 
ECG 
electrocardiogram 


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ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EGA 
EDTA/glycine-acid 
EDC 
electronic data capture 
ELISA 
enzyme linked immunosorbent assay 
EOT 
End of Treatment 
ESC 
European Society of Cardiology 
FDA 
Food and Drug Administration 
GCIG 
Gynecologic Cancer InterGroup 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ICU 
intensive care unit 
IEC 
Independent Ethics Committee 
INFg 
interferon gamma 
INR 
international normalized ratio 
irPD 
progressive disease according to irRECIST (Bohnsack 2014) 
irRECIST 
Guidelines for the Evaluation of Immune Therapy Activity in Solid 
Tumors:  Immune-related Response Criteria 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IUD 
intra-uterine device 
IUS 
intra-uterine hormone-releasing system 
IV 
intravenous 
kg 
kilogram 
KM 
Kaplan-Meier 
L 
liters 
LDH 
lactate dehydrogenase 
LHRH 
luteinizing-hormone releasing hormone 
LISS 
low ionic strength solution 
LTFU 
long-term follow-up 
LPE 
last patient enrolled 


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LSC 
leukemic stem cells 
M1 
macrophages that suppress tumor progression 
M2 
macrophages that promote tumor progression 
mAb 
monoclonal antibody 
MCC 
Merkel cell carcinoma 
MDS 
myelodysplastic syndrome 
MedDRA 
Medical Dictionary of Regulatory Activities 
mg 
milligram 
MHRA 
Medicines and Healthcare products Regulatory Agency (UK) 
MOA 
mechanism of action 
mRNA 
messenger ribonucleic acid 
MTD 
maximum tolerated dose 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NHL 
non-Hodgkin’s lymphoma 
NSG 
NOD/SCID/IL2R gamma null 
NYHA 
New York Heart Association 
ORR 
overall response rate 
OS 
overall survival 
PARP 
inhibitors 
polyadenosine-diphosphate ribose polymerase inhibitors 
PAS 
Pharmacokinetic Analysis Set 
PD 
progressive disease 
PD-1 
programmed cell death-protein 1 
PD-L1 
programmed cell death-ligand 1 
PeG 
polyethylene glycol 
PFI 
platinum-free interval 
PFS 
progression-free survival 
PI 
Prescribing Information 
PK 
pharmacokinetic(s) 
PR  
partial response 
PRBC 
packed red blood cell (transfusions) 
PT 
prothrombin time 
RANKL 
receptor activator of nuclear factor kappa-B ligand 
RBC 
red blood cell 
REC 
Research Ethics Committee 


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RECIST 
Response Evaluation Criteria in Solid Tumors 
Rh 
Rhesus factor 
RO  
Receptor Occupancy 
RP2DS 
recommended Phase 2 dose and schedule 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Safety Analysis Set 
SD 
stable disease 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SIRPα 
signal regulatory protein alpha 
SOA 
Schedule of Assessments 
S-P 
Ser-Pro 
T3 
triiodothyronine 
T4 
thyroxine 
TEAE 
treatment-emergent adverse event 
TSH 
thyroid stimulating hormone 
TTP 
time to tumor progression 
UK 
United Kingdom 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cell 


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1. BACKGROUND 
1.1. 
Ovarian Cancer 
Ovarian cancer is the most frequent cause of gynecologic cancer deaths in the 
United States (US).  Standard of care for this disease in the frontline and 
platinum-sensitive recurrent setting is platinum-based chemotherapy with or without 
antiangiogenic agents.  More recently, targeted agents such as poly 
adenosine-diphosphate ribose polymerase (PARP) inhibitors have been approved 
by the Food and Drug Administration (FDA) for women with breast cancer 
susceptibility gene (BRCA) mutations and/or alterations in the homologous 
recombination pathway.  Experience with newer immunotherapies in this disease, 
such as the checkpoint inhibitors, has not yet matured to impact clinical outcomes.  
In women with recurrent ovarian cancer, the platinum-free interval (PFI), defined as 
the interval between the last platinum dose and the date of relapse (Rustin 2011), is 
strongly correlated with the likelihood of response to subsequent chemotherapy.  
Patients who initially respond to systemic therapy with a PFI greater than 1 month, 
but less than 6 months, have been historically referred to as platinum-resistant, and 
these patients have limited treatment options (Davis 2014).  Thus, the development 
of effective cancer treatments for this patient population would address a substantial 
unmet medical need. 
1.2. 
Study Drug:  Hu5F9-G4, a CD47-Blocking Antibody 
1.2.1. 
CD47 Biology 
CD47 is a widely-expressed cell surface protein that regulates phagocytosis 
mediated by cells of the innate immune system such as macrophages and dendritic 
cells.  CD47 binds to and activates a receptor on innate immune cells, signal 
regulatory protein alpha (SIRPα), which initiates a signal transduction cascade that 
blocks phagocytosis.  In this way, CD47 functions as a dominant inhibitor of 
phagocytosis by delivering a potent “don’t eat me” signal to phagocytic cells 
(Blazar 2001; Okazawa 2005).  However, the complex process of phagocytosis 
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Most normal cells, apart from aging red blood cells (RBCs) 
(Okazawa 2005; Oldenborg 2000), lack expression of corresponding pro-phagocytic 
signals (Chao 2012; Jaiswal 2009; Majeti 2009), and, thus, are unaffected by CD47 
blockade.  In contrast, most cancer cells express pro-phagocytic signals on their cell 
surface, many of which are not yet molecularly characterized (Chao 2011b; 
Chao 2012).  As a consequence, effective phagocytosis requires two distinct events: 
a silenced CD47/SIRPα pathway coupled with a pro-phagocytic signal. 
CD47 is overexpressed in a broad range of human tumors, including ovarian cancer.  
The Weissman and Majeti laboratories originally identified increased CD47 
expression on leukemic stem cells (LSC) in human acute myeloid leukemia (AML) 
(Chao 2010b; Majeti 2009).  The increased expression of CD47 on cancer cells is 
presumed to prevent their phagocytic elimination by innate immune cells 
(Jaiswal 2009; Majeti 2009).  These observations have since been extended to a 
diverse range of hematologic and solid tumor malignancies.  Analysis of patient 
tumor and matched adjacent normal (non-tumor) tissue revealed that CD47 is 
overexpressed by approximately 3.3-fold in a panel of solid tumors including ovarian, 
breast, bladder, glioblastoma, hepatocellular, prostate, and colon cancer 
(Willingham 2012).  In 2 distinct datasets derived from patients with ovarian cancer, 
tumor CD47 messenger ribonucleic acid (mRNA) expression levels correlated with 
worse progression-free survival (PFS) and overall survival (OS), as shown in 
Figure 1-1. 


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Figure 1-1. 
CD47 mRNA Expression Levels May be a Prognostic Factor 
 
Source:  Willingham 2012. 
A = Data from 269 ovarian cancer patients, hazard ratio for progression-free survival (PFS) = 2.1 
(95% confidence interval [CI]:  1.3—3.3). 
B = Data from 83 ovarian cancer patients, hazard ratio for PFS = 6.6 (95% CI:  2.1—20.8). 
 
CD47 appears to be an indispensable means by which cancer cells, including 
cancer stem cells, overcome intrinsic expression of their pro-phagocytic, “eat me,” 
signals (Chao 2010b; Chao 2012).  When CD47 is blocked from interacting with 
SIRPα (e.g., using an antibody to CD47), these pro-phagocytic signals dominate, 
enabling phagocytosis of the cancer cells, which results in the inhibition of tumor 
growth and metastasis (Chao 2011b; Chao 2010a; Edris 2012a; Edris 2012b; 
Kim 2012; Majeti 2009; Willingham 2012; Liu 2015b).  In addition to this direct 
anti-tumor effect, CD47 blockade also has the potential to induce an adaptive 
anti-tumor T-cell response through the cross-presentation of tumor antigens by 
macrophages and antigen-presenting cells following phagocytosis (Tseng 2013; 
Liu 2015a).  Thus, the inhibition of CD47 signaling is a promising therapeutic 
strategy for targeting tumors using the innate and adaptive immune systems. 
Most normal cells lack expression of pro-phagocytic signals and are unaffected by 
CD47 blockade.  RBCs are a notable exception because CD47 expression protects 
RBCs from elimination by splenic red pulp macrophages, as well as sinusoidal 
macrophages, in liver and bone marrow.  As RBCs age, they gradually lose CD47 
expression and reorganize membrane phospholipids in a manner that enhances 
pro-phagocytic signaling, ultimately leading to their elimination by phagocytosis.  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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The Weissman laboratory explored the effect of CD47 blockade on erythrocytes in 
primates by using monoclonal antibodies that bind to and inhibit CD47 signaling 
(Liu 2015b).  Administration of CD47-blocking antibodies accelerates the phagocytic 
process by substituting gradual loss of CD47 with immediate blockade of CD47 on 
aging RBCs, changing the balance between anti-phagocytic and pro-phagocytic 
signals in the RBC pool.  In nonclinical studies, the premature loss of aging RBCs is 
compensated by an ensuing reticulocytosis, and the initial anemia resolves as aged 
RBCs are replaced with younger cells.  Furthermore, in non-human primates, the 
risk of severe anemia is mitigated by the initial administration of a low, priming dose 
of anti-CD47 antibody that results in mild-to-moderate anemia and stimulates 
reticulocytosis.  In summary, antibody blockade of the CD47/SIRPα pathway serves 
as a promising therapeutic strategy in cancer. 
1.2.2. 
Hu5F9-G4 
Hu5F9-G4 is a humanized anti-human IgG4 monoclonal antibody (mAb) that binds 
to CD47 and blocks its interaction with its receptor, enabling phagocytosis of human 
cancer cells (Liu 2015b).  The activity of Hu5F9-G4 is primarily dependent on 
blocking CD47 binding to SIRPα and not on the recruitment of Fc-dependent effector 
functions, although the presence of the IgG4 Fc domain is required for its full activity.  
For this reason, Hu5F9-G4 was engineered with a human IgG4 isotype that is 
relatively inefficient at recruiting Fc-dependent effector functions that might enhance 
toxic effects on normal CD47 expressing cells (Liu 2015b).  Preclinical studies using 
xenograft cancer models provide compelling evidence that Hu5F9-G4 triggers 
phagocytosis and elimination of cancer cells from human solid tumors and 
hematologic malignancies (Liu 2015b).  Based on this mechanism of action (MOA) 
and its potent preclinical activity, Hu5F9-G4 is being developed as a novel 
therapeutic candidate for solid tumors and hematologic malignancies. 
1.2.3. 
Preclinical Studies 
In preclinical models, anti-CD47 antibodies demonstrate anti-tumor activity against a 
broad range of human solid tumors (breast, ovarian, colon, glioblastoma and others) 


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(Willingham 2012; Edris 2012a) and hematologic malignancies (AML, acute 
lymphoblastic anemia [ALL], non-Hodgkin's lymphoma [NHL], myeloma, and others) 
(Majeti 2009; Chao 2011a; Chao 2010a; Chao 2011b; Kim 2012). In ovarian cancer 
laboratory models, anti-CD47 antibodies enhance the in vitro phagocytosis of 
ovarian cancer stem cells by macrophages and they also inhibit the in vivo growth of 
engrafted ovarian tumor cells (Figure 1-2). 
Figure 1-2. 
Anti-CD47 Antibody Therapy Eliminates Ovarian Cancer 
Cells In Vivo and Cures Mice Xenografted with Patient 
Ovarian Cancer 
Anti-CD47 monoclonal antibodies (mAbs) inhibit tumor growth as measured by bio-luminescence 
activity (Left Panel) and improve survival (Right Panel) of NOD/SCID/IL2R gamma null (NSG) mice 
engrafted with ovarian cancer (Willingham 2012). 
1.2.4. 
Hu5F9-G4 Clinical Studies 
1.2.4.1. 
Summary of Hu5F9-G4 Clinical Safety 
As of 24 July 2017, a total of 92 patients have been treated with Hu5F9-G4 both as 
monotherapy and in combination. Dose levels evaluated to date are described in 
Section 1.6.1 , Starting Dose Rationale. 
Two monotherapy Phase 1 clinical trials are ongoing. The first-in-human study, 
Study SCI-CD47-001 , is a Phase 1 dose escalation trial of Hu5F9-G4 in patients 
with advanced solid tumors and lymphomas. The Phase 1 study was designed to 
determine the optimal dose and schedule of Hu5F9-G4 and to characterize its 
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preliminary safety, pharmacokinetics (PK), and pharmacodynamics.  As of 24 July 
2017, this trial has treated 58 patients and dose escalation is ongoing.  The second 
study, Study SCI-CD47-002, is a Phase 1 trial in patients with relapsed or refractory 
AML and subsequently relapsed or refractory myelodysplastic syndrome (MDS).  
The second study was initiated to define the maximum tolerated dose (MTD) and to 
evaluate the safety, PK, and pharmacodynamics of Hu5F9-G4 in this patient 
population.  This trial has treated 14 patients as of 24 July 2017 and it is also 
ongoing. 
In monotherapy trials with Hu5F9-G4, the most common clinically relevant 
non-serious adverse drug reaction is an acute mild anemia observed after the first 
dose of study drug.  This clinical observation is consistent with the known MOA of 
Hu5F9-G4 and the physiologic role of CD47 in regulating the turnover of aging 
erythrocytes.  However, in solid tumor and lymphoma patients, the clinical impact of 
this anemia has been substantially mitigated using a priming and maintenance 
dosing strategy.  After an initial priming dose of 1 mg/kg of Hu5F9-G4 administered 
intravenously (IV) on Day 1 of Week 1, a rapid, predictable fall in hemoglobin level of 
1.5 to 2 g/dL on average is observed during the first 1 to 2 weeks of treatment.  
Beginning in Week 2, substantially higher maintenance doses of Hu5F9-G4 can be 
administered with no further effects on RBCs.  In solid tumor and lymphoma 
patients, this mild acute anemia is followed by a rapid, compensatory reticulocytosis 
and a gradual return of hemoglobin levels to baseline by Week 3 or 4, despite 
continued dosing.  In patients with AML with significant disease bone marrow 
infiltration, a similar mild acute anemia with an average hemoglobin decrement of 
0.5 to 2 g/dL is observed; however, these patients are easily managed with RBC 
transfusions despite continued treatment with Hu5F9-G4.  Other laboratory 
abnormalities associated with Hu5F9-G4 including reticulocytosis, spherocytosis, 
transient hyperbilirubinemia (predominantly unconjugated), and decreased 
haptoglobin are all indicative of extravascular hemolysis consistent with phagocytic 
removal of RBCs after CD47 blockade. 


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Another erythrocyte-associated drug effect is hemagglutination, which typically 
occurs within 24 hours of the first or second dose of Hu5F9-G4.  In solid tumor 
patients, this transient hemagglutination is observed less frequently beyond the first 
1 or 2 infusions.  The clinical relevance of this hemagglutination is uncertain, as it 
has not been correlated with any clinical signs or symptoms.  Because RBC 
agglutination may be related to the rapid rise in Hu5F9-G4 concentrations in 
treatment-naïve patients, the duration of the initial priming dose infusion may have 
relevance.  In solid tumor patients, a single 1-hour priming dose infusion of 1 mg/kg 
of Hu5F9-G4 was associated with hemagglutination in 6 out of 6 patients.  However, 
when the duration of the 1 mg/kg priming dose was extended to 3 hours in 
subsequent patients, hemagglutination only occurred in 6 out of 14 patients.  
Currently, a 3-hour priming dose infusion duration is being used in all solid tumor 
and lymphoma patients; however, a shorter 2-hour infusion duration is being used 
for subsequent maintenance doses.  In the AML trial, a 3-hour infusion is being used 
for all Hu5F9-G4 doses ≥1.0 mg/kg. 
Other common treatment-related adverse events (AEs) include headache, fatigue, 
nausea, photopsia, urine discoloration, low back pain, and abdominal pain.  
Common drug-related abnormal laboratory findings include transient reticulocytosis, 
spherocytosis, hyperbilirubinemia (predominantly unconjugated), D-dimer elevation, 
and decreased haptoglobin.  In solid tumor patients, the D-dimer elevation has not 
been any associated with any signs of disseminated intravascular coagulation, 
thrombocytopenia, coagulopathy, microangiopathy, or thromboembolic disease.  
The majority of these findings occur following the first infusion with relatively fewer 
drug-related toxicities reported beyond the first cycle.  In solid tumor patients, 
maintenance doses of up to 30 mg/kg once weekly have been explored with dose 
escalation continuing.  Since the adoption of an Hu5F9-G4 priming and maintenance 
dosing strategy, no MTD level has been identified.  In AML patients, twice-weekly 
treatments with Hu5F9-G4 coupled with an intrapatient dose escalation scheme has 
also been well tolerated with no dose-limiting toxicities (DLTs) being reported to 
date.  Dose escalation is also ongoing in the AML Phase 1 trial. 


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Two combination clinical trials have been initiated with Hu5F9-G4.  The first study 
(Study 5F9003) has treated 11 patients with NHL in combination with rituximab, 
while the second (Study 5F9004) has treated 9 colorectal cancer (CRC) or solid 
tumor patients with Hu5F9-G4 and cetuximab.  Both of these combination studies 
are continuing to escalate the doses of these agents in combination; an MTD has 
not been reached.  As of 24 July 2017, no new major toxicities of these 
combinations have been observed, and there is no evidence that Hu5F9-G4 alters 
the toxicity profile of rituximab or cetuximab. 
1.2.4.2. 
Summary of Hu5F9-G4 Clinical Pharmacology 
No formal clinical pharmacology trials have been completed with Hu5F9-G4; 
however, PK samples are being gathered from all patients in all ongoing studies 
after single and multiple doses.  As of October 2017, approximately 1200 PK 
samples from 58 patients in the ongoing solid tumor Phase 1 study (SCI-CD47-001) 
had been analyzed using a validated enzyme-linked immunosorbent assay (ELISA).  
Samples are from Parts A, B, or C of the protocol.  Hence, all patients were 
administered a single dose of 1 mg/kg (or less in Part A) on Day 1 of Week 1 
followed by the target dose (1, 3, 10, 20, or 30 mg/kg once weekly, thereafter) from 
Day 8 onward.  Patients in Part C received 2 doses of Hu5F9-G4 20 or 30 mg/kg in 
the week after priming dose followed by 20 or 30 mg/kg weekly afterwards.  Overall, 
the data indicated nonlinearity in the PK profiles over the dose range 0.3–30 mg/kg; 
the terminal half-life was higher at the higher doses of 10–30 mg/kg compared to the 
lower doses indicating potential target-mediated drug disposition.  Drug exposures 
were dose-proportional at doses ≥10 mg/kg and a typical antibody-like profile with 
extended half-life was seen at these doses. 
The PK also showed time-variance between the first and second doses at the dose 
of 1 mg/kg.  After the first dose of 1 mg/kg the maximum concentration (Cmax) was 
approximately 0.7 mcg/mL, whereas that after the second dose of 1 mg/kg was 
approximately 10-fold higher.  On subsequent dosing, there were no further changes 
in the PK at this dose level.  Furthermore, at higher doses (3, 10, 20, and 30 mg/kg), 
the PK profile was roughly similar after the second and fifth doses, suggesting that 


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the time-variant PK only occurred at 1 mg/kg between the first and second weekly 
doses. 
As of June 2017, in the solid tumor Phase 1 study, 2 of 41 patients (4.87%) treated 
tested positive for anti-drug antibodies (ADA) against Hu5F9-G4.  In AML 
(Study SCI-CD47-002), 1 out of 13 patients (7.69%) had confirmed ADA samples, 
but the impact on drug PK could not be ascertained due to the limited amount of 
available PK data.  The samples have not yet been tested for neutralizing 
antibodies.  No unusual clinical toxicities have been observed in the patients with 
positive ADAs. 
1.2.4.3. 
Summary of Hu5F9-G4 Clinical Efficacy 
In the ongoing solid tumor Phase 1 clinical trial (SCI-CD47-001), 5 patients with 
advanced ovarian cancer or related gynecologic tumors have been treated with 
doses of Hu5F9-G4 of 20 mg/kg or higher.  Doses of 20 and 30 mg/kg generate 
consistent trough Hu5F9-G4 serum concentrations greater than 100 mcg/mL, which 
was the minimum concentration threshold associated with preclinical anti-tumor 
activity (Forty Seven Inc., data on file).  Four of these five patients demonstrated a 
fall in CA125, commensurate with the start of Hu5F9-G4 monotherapy.  Two of 
these patients had confirmed objective partial responses (PRs).  Both were heavily 
pretreated with 
 including 
 
.  One patient was a 
 woman with 
 
 whose CA125 decreased from 
 and who also had a 
 
 tumor measurements on her initial 
 
restaging scans.  She remained on study 
 before progression of 
disease.  The second patient was a 
 woman with 
 
who had a decrease in CA125 from 
 and demonstrated a 
.  She remains on active treatment for 
.  Of the 3 remaining ovarian cancer patients, 2 had stable disease (SD) 
and 1 had progressive disease (PD) as their best RECIST responses.  Hu5F9-G4 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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shows monotherapy activity in ovarian and related gynecologic cancers; thus, an 
expansion of the clinical experience in this disease setting is warranted. 
In Study SCI‐CD47‐002, 2 patients with relapsed/refractory AML treated with 
Hu5F9-G4 10 mg/kg administered twice weekly have demonstrated marked 
reduction in bone marrow cellularity after 4 weeks of treatment.  One of these 
patients also had a greater than 50% reduction in the percent AML blasts in the 
bone marrow and this patient remains stable on treatment for over 44 weeks.  
Interestingly, this same patient demonstrated an increase in bone marrow infiltration 
by CD3-positive lymphocytes from 10–15% to 40–50% of bone marrow cells by 
Day 53 of treatment.  This provides preliminary support for the hypothesis that 
CD47-blockade with Hu5F9-G4 may enhance an adaptive T-cell response to tumor 
antigens.  Such observations support the clinical evaluation of Hu5F9-G4 in 
combination with programmed cell death-ligand 1 (PD-L1) checkpoint inhibitors in 
clinical trials. 
Early evidence of anti-tumor activity for Hu5F9-G4 in combination with anti-tumor 
antibodies is also emerging.  In the 5F9003 NHL combination study, a heavily 
pretreated patient with follicular lymphoma treated with 10 mg/kg of Hu5F9-G4 
combined with standard doses of rituximab achieved a complete response (CR) and 
has remained on treatment for longer than 39 weeks.  In addition, objective 
anti-tumor responses were observed in 2 patients with diffuse large B-cell lymphoma 
(DLBCL) treated with 20 mg/kg of Hu5F9-G4 and rituximab including a CR and a 
PR.  Both previously received rituximab-containing regimens.  Finally, in the 5F9004 
solid tumor/CRC study, 1 CRC patient treated with 10 mg/kg of Hu5F9-G4 with 
400/250 mg/m2 of cetuximab has achieved a confirmed PR.  Dose escalation in both 
the NHL and CRC combination trials are ongoing.  These emerging data suggest 
that combination regimens with Hu5F9-G4 are well tolerated and have potential for 
therapeutic benefit in patients with solid tumors and lymphomas.  Thus, exploration 
of additional novel Hu5F9-G4 combinations with other monoclonal antibodies, 
including PD-L1 inhibitors, is warranted. 


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1.3. 
Preclinical Combination Studies 
Antibodies such as avelumab with an active Fc component may be optimal for 
combining with anti-CD47 targeting agents.  Avelumab can bind to PD-L1 on the 
surface of cancer cells, thereby providing an exogenous pro-phagocytic signal that 
can be augmented by CD47 blockade.  In contrast, anti-PD-L1 antibodies that lack 
Fc component activity and anti-programmed cell death-protein 1 (PD-1) antibodies 
that do not bind directly to cancer cells do not provide enhancement of pro-
phagocytic signals.  This is demonstrated in preclinical studies, showing that the 
combination of avelumab with Hu5F9-G4 enhances antibody-dependent cellular 
phagocytosis (ADCP) of PD-L1 expressing ES-2 ovarian cancer cells (Forty Seven 
Inc., data on file; Figure 1-3, left panel).  This occurs both at baseline and after 
treatment of cancer cells with interferon gamma (INFg) to enhance PD-L1 
expression.  However, when checkpoint signaling is blocked using other inhibitors 
such as an anti-PD-L1 antibody with a “dead” Fc component or an anti-PD-1 
antibody that does not bind cancer cells, no enhancement of phagocytosis occurs in 
combination with Hu5F9-G4 (Figure 1-3, right panel).  In contrast to avelumab, these 
other PD-L1/PD-1 inhibitors cannot provide additional pro-phagocytic signals.  
Currently this combination with avelumab has only been evaluated in this ovarian 
cancer model, but it has the potential to apply to other tumor types as well.  These 
data suggest that the unique combination of Hu5F9-G4 with avelumab may have 
additional beneficial anti-tumor properties that can be explored in the clinical setting. 


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Figure 1-3. 
Avelumab but Not Other Checkpoint Inhibitor Antibodies 
Enhance Phagocytosis of Cancer Cells in Combination with 
Hu5F9-G4 
 
Source:  Forty Seven Inc., Report Numbers FSI-2017-004 and FSI-2017-005. 
Abbreviations:  IFNg = interferon gamma; PD-L1 = programmed death ligand-1. 
 
1.4. 
Translational Studies Background 
Blockade of the CD47-SIRPα signaling axis on tumor cells by a monoclonal 
anti-CD47 antibody could lead to tumor elimination by activation of both the innate 
and adaptive immune system.  The anti-tumor activity of CD47 blocking antibodies is 
mediated by macrophages and other phagocytic cells of the innate immune system.  
Macrophages are a common immune cell infiltrate in many tumor types, with degree 
of intra-tumoral macrophage infiltrate correlating with clinical prognosis. 
The correlation between macrophage infiltration and clinical disease course is often 
dependent on the presence of either classically activated (M1) type macrophages 
that suppress tumor progression or alternatively, activated (M2) type macrophages 
that promote tumor progression (Pollard 2004).  Given the frequent infiltration of 
  
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 


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M2 macrophages in many tumor types and its role in promoting tumorigenesis, there 
is widespread interest in developing therapies that shift tumor macrophage 
polarization from the pro-tumorigenic M2 to the anti-tumorigenic M1 macrophages.  
In preclinical studies, anti-CD47 antibody-mediated tumor cell phagocytosis has 
been demonstrated to occur through both M1 and M2 macrophages (Zhang 2016).  
In addition, in vivo treatment of human xenograft tumors with anti-CD47 antibody 
demonstrated increased M1 intratumoral macrophages post-treatment 
(Zhang 2016), suggesting that anti-CD47 antibody can also shift the phenotype of 
macrophages from the M2 towards the M1 phenotype in vivo.  Because the 
recruitment of macrophage effector cells is a key mechanism of anti-tumor activity 
for anti-CD47 antibodies, the characterization of macrophage tumor infiltration 
pre- and post-treatment may provide important insights into the degree of potential 
benefit seen in different patients and across various cancer subtypes. 
In addition to modulating the innate immune system, anti-CD47 antibody therapy 
also activates the adaptive immune system towards an anti-tumor response.  
Phagocytosis of tumor cells by phagocytes (macrophages and/or dendritic cells) 
leads to cross-presentation of tumor antigens to T cells, enabling a T cell anti-tumor 
response (Tseng 2013; Liu 2015b).  In one preclinical study, anti-CD47 antibody 
mediated a specific CD8 T cell anti-tumor response without proliferation of regulatory 
T cells (which are generally thought to be tumor-promoting) (Tseng 2013).  
Currently, there is intense interest in investigating the relationship between T cell 
subsets that infiltrate the tumor and clinical response with the use of 
immune-oncology therapeutics.  Increased T cell infiltration in the tumor has been 
associated with clinical response in oncology patients treated with T cell checkpoint 
inhibitors (Tumeh 2014; Herbst 2014).  Given the role of anti-CD47 antibody in 
mediating an anti-tumor T cell response, the clinical investigation of the contribution 
of T cell effectors to anti-CD47 antibody-mediated efficacy is important to define how 
the innate and adaptive immune systems interact in various patients. 


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1.5. 
Avelumab 
The PD-1 receptor and PD-1 ligands 1 and 2 (PD-L1, PD-L2) play integral roles in 
immune regulation.  Expressed on activated T cells, PD-1 is activated by PD-L1 and 
PD-L2 expressed by stromal cells, tumor cells, or both, initiating T-cell death and 
localized immune suppression (Dong 1999; Freeman 2000; Dong 2002; Topalian 
2012a), potentially providing an immune-tolerant environment for tumor development 
and growth.  Conversely, inhibition of this interaction can enhance local T-cell 
responses and mediate anti-tumor activity as demonstrated in nonclinical animal 
models (Dong 2002; Iwai 2002). 
In the clinical setting, treatment with antibodies that block the PD-1–PD-L1 
interaction have been reported to produce objective response rates of 7% to 38% in 
patients with advanced or metastatic solid tumors, with tolerable safety profiles 
(Brahmer 2012; Topalian 2012b; Hamid 2013).  Notably, responses appeared 
prolonged, with durations of 1 year or more for the majority of patients. 
Avelumab is a fully human monoclonal antibody of the immunoglobulin (Ig) G1 
isotype.  This anti-PD-L1 therapeutic antibody concept is being developed in 
oncological settings by Merck KGaA (Darmstadt, Germany), its subsidiary, EMD 
Serono Research & Development Institute, Inc. (Billerica, MA, USA), and by Pfizer, 
Inc. (New York, NY, USA). 
Avelumab selectively binds to PD-L1 and competitively blocks its interaction with 
PD-1.  Compared with anti-PD-1 antibodies that target T-cells, avelumab targets 
tumor cells.  It is therefore hypothesized to have fewer side effects, including a lower 
risk of autoimmune-related safety issues, since the blockade of PD-L1 leaves the 
PD-L2 / PD-1 pathway intact to promote peripheral self-tolerance (Latchman 2001).  
For additional details from the in vitro and nonclinical studies, refer to the current 
Avelumab Investigator’s Brochure (Avelumab IB). 
Avelumab is currently in clinical development in several ongoing Phase 1 to 3 clinical 
trials.  Avelumab is being investigated as a monotherapy or in combination with 
other anti-cancer treatments in patients with different types of malignancies. 


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The clinical experience of avelumab, including its clinical activity, safety, PK, and 
pharmacodynamics, is currently based largely on data from Trial EMR100070-001, 
which is a Phase 1, open-label, multicenter trial being conducted in over 
1600 patients with solid tumors.  Study EMR100070-001 has 2 phases, a dose 
escalation phase and a treatment expansion phase, the latter recruiting patients in 
16 different solid tumor expansion cohorts. 
Avelumab exposure parameters, including the Cmax and the area under drug 
concentration curve (AUC), generally increased in an approximately 
dose-proportional manner.  The terminal half-life of avelumab increased with 
avelumab doses.  There was little accumulation of avelumab, which was consistent 
with the short half-life of avelumab. 
Clinical activity with avelumab has been observed in patients with different types of 
solid tumors.  In patients with recurrent or refractory ovarian cancer, avelumab 
demonstrated an acceptable safety profile and evidence of clinical activity 
(Disis 2016).  In 124 women participating in an ongoing Phase 1b avelumab study, 
12 achieved PR (9.7%) and 55 achieved SD (44.4%).  The median PFS was 
11.3 weeks and the OS was 10.8 months.  Additional details are provided in the 
Avelumab IB.  In addition, two large Phase 3 trials of avelumab in ovarian cancer are 
ongoing.  The first is a study of avelumab either in combination with or following 
carboplatin and paclitaxel chemotherapy in previously untreated epithelial ovarian, 
fallopian tube cancer, or primary peritoneal cancer patients (JAVELIN Ovarian 100; 
NCT02718417; Appendix A). 
Available safety data for the avelumab program, which are summarized in the 
current IB, demonstrate an acceptable safety profile with 10 mg/kg of avelumab. 
The safety data from patients with different tumor types treated with avelumab 
suggest an acceptable safety profile of the compound.  Most of the observed events 
were either in line with those expected in patients with advanced solid tumors or with 
similar class effects of mAb blocking the PD-1/PD-L1 axis.  Infusion-related 
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reactions (immune-related pneumonitis, immune-related colitis, immune-related 
hepatitis, immune-related endocrinopathies [thyroid disorders, adrenal insufficiency, 
new onset type I diabetes mellitus, pituitary disorders]), immune-related nephritis 
and renal dysfunction, and other immune-related AEs (myositis, myocarditis, 
Guillain-Barré syndrome, uveitis) have been identified as important risks for 
avelumab.  Detailed guidelines for the management of immune-related adverse 
events and infusion-related reactions have been implemented in all ongoing clinical 
studies with avelumab, including the current protocol (Section 6.5.2). 
1.6. 
Starting Dose Rationale 
1.6.1. 
Hu5F9-G4 Dose 
The following starting Hu5F9-G4 dosing scheme is proposed for this study:  In Cycle 
1, a priming dose of 1 mg/kg on Day 1 of Week 1, followed by doses of 30 mg/kg on 
Day 8, 15, 22, 29 (Weeks 2-5).  This is followed by doses of 30 mg/kg Q2W on Days 
1 and 15 beginning in Cycle 2. 
The safety and PK of Hu5F9-G4 has been explored in solid tumor and lymphoma 
patients using a priming and maintenance dose schedule (Forty Seven Inc., data on 
file; Section 1.2.4).  In the ongoing solid tumor Phase 1 study, a dosing schedule 
that includes an initial priming dose of 1 mg/kg administered on Day 1 of Week 1, 
with 2 subsequent doses of 30 mg/kg in Week 2, followed by weekly doses of 
30 mg/kg beginning in Week 3, has been demonstrated to be safe as monotherapy.  
No maximum tolerated dose (MTD) has been reached in any study with up to 
45 mg/kg of weekly dosing as monotherapy (Study SCI-CD47-001; data on file at 
Forty Seven Inc.).  Additionally, Hu5F9-G4 has been well-tolerated in combination 
with other monoclonal antibodies (including rituximab and cetuximab) with no MTD 
reached with up to 30 mg/kg of weekly dosing.  After priming doses of 1 mg/kg, 
mean reduction of approximately 2 g/dL in hemoglobin was observed, followed by a 
rapid associated reticulocytosis.  CD47 receptor occupancy (RO) assays also 
confirmed near 100% occupancy of CD47 on RBCs by Hu5F9-G4 at this dose.  
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In the solid tumor study (Study SCI-CD47-001), at doses of 30 mg/kg of circulating 
Hu5F9-G4, drug concentrations were in the range of 400–1500 mcg/mL by the end 
of the first cycle—far exceeding concentrations associated with anti-tumor efficacy in 
preclinical xenograft models (100 mcg/mL; Forty Seven Inc. data on file) and also 
higher than the concentrations at 20 mg/kg (250–900 mcg/mL), which was 
associated with objective responses in 2 patients.  Population PK modelling and 
simulation predicts that with the proposed dosing regimen of 30 mg/kg weekly 
loading doses followed by 30 mg/kg every 2 weeks maintenance doses, the 
steady-state concentrations will be in the range of 300 to 1000 mcg/mL.  This 
concentration range has been associated with objective response in 2 patients with 
ovarian cancer in Study SCI-CD47-001.  Model-predicted and observed receptor 
occupancy on peripheral white blood cells (WBCs) at these concentrations was 
near maximal.  The dose regimen of 30 mg/kg of Hu5F9-G4 every 2 weeks starting 
in Cycle 2 proposed for this study is expected to achieve optimal impact on the 
molecular target and be both safe and efficacious. 
This study proposes to evaluate the dose regimen described above, which is the 
recommended Phase 2 dose of Hu5F9-G4, in combination with standard approved 
doses of avelumab in a 12-patient Safety Run-in Cohort.  If the safety of this 
combination is confirmed, the regimen will be evaluated further in an expansion 
cohort of 20 ovarian cancer patients.  No synergistic toxicities for the 2 agents in 
combination are anticipated; however, if DLTs are observed at the initial starting 
dose, dose de-escalation of Hu5F9-G4 may be explored (as described in Section 3) 
to define an MTD. 
Further dose escalation to 45 mg/kg was performed in six patients and considered 
safe with no DLT’s in Study SCI-CD47-001.  As such, if no DLTs are reported and 
Dose Level 1 is considered safe, the dose of Hu5F9 may be escalated to 45 mg/kg.  
(See Table 3-1) in Part A.  The CTSC may recommend one or multiple doses and 
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1.6.2. 
Avelumab Dose 
To date, avelumab has been administered at the clinically active tolerable dose of 
10 mg/kg every 2 weeks to more than 1800 patients across multiple indications.  
Furthermore, this 10 mg/kg every-2-week avelumab dosing regimen has been 
approved by the FDA as the first treatment for Merkel Cell Carcinoma and Urothelial 
Carcinoma.  Avelumab was originally dosed on a mg/kg basis in order to reduce 
inter participant variability in drug exposure.  However, emerging data for 
monoclonal antibodies, including the marketed PD-1 and PD-L1 immune checkpoint 
inhibitors nivolumab, pembrolizumab, and atezolizumab, reveal that body 
weight-based dosing regimens do not result in less variability in measures of 
exposure over fixed (i.e., body-weight independent) dosing regimens (Wang 2009; 
Freshwater 2017; Zhao 2017).  Additionally, fixed dosing offers the advantages of 
less potential for dispensing errors, shorter dose preparation times in a clinical 
setting, and greater ease of administration. 
Population PK analysis was conducted based on the acquired data across 
3 single-agent avelumab studies in more than 1700 patients with 14 different types 
of cancer.  Pharmacokinetic simulations suggest that exposures to avelumab across 
the available range of body weights are less variable with 800 mg every 2 weeks 
compared with 10 mg/kg every 2 weeks; exposures were similar near the population 
median weight.  Low-weight participants tended towards marginally lower exposures 
relative to the rest of the population when weight-based dosing was used, and 
marginally higher exposures when flat dosing was applied.  However, the 
implications of these exposure differences are not expected to be clinically 
meaningful at any weight across the entire population.  Furthermore, the 800 mg 
every 2-week dosing regimen is expected to result in Ctrough > 1 μg/mL required to 
maintain avelumab serum concentrations at > 95% target occupancy throughout the 
entire 2-week dosing interval in all weight categories. 
Therefore, in this clinical study, a fixed dosing regimen of 800 mg administered as 
1-hour IV infusion every 2 weeks will be used for avelumab. 


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1.7. 
Study Rationale and Risk-Benefit 
Patients with advanced ovarian cancer who have relapsed or are resistant or 
refractory to platinum-based chemotherapy have limited options for effective 
treatment and an overall poor prognosis (Davis 2014).  Consequently, a 
well-tolerated immunotherapy combination that can induce anti-tumor responses and 
prolong PFS and OS would be an important therapeutic advance in the management 
of disease in these patients.  Preliminary clinical data from Hu5F9-G4 monotherapy 
in patients with solid tumors suggest that blockade of CD47 may induce objective 
responses in heavily pretreated patients with ovarian cancer.  Furthermore, 
preclinical studies and our understanding of the mechanism of Hu5F9-G4 action 
suggest that targeting CD47 may generate substantial synergistic anti-tumor activity 
when combined with PD-L1 checkpoint inhibitors.  Thus, the scientific rationale for 
exploring the efficacy of this combination in this setting is strong. 
The clinically relevant overlapping toxicities that have been observed for both 
Hu5F9-G4 and avelumab are infusion-related reactions and immune-related AEs.  
Single-agent toxicity data are summarized in Section 1.2.4.1 for Hu5F9-G4 and in 
Section 1.5 for avelumab.  The safety risk of the proposed combination is not 
anticipated to be greater than that associated with the use of either of these agents 
as monotherapy.  However, because the preclinical safety experience with this 
combination is limited and there is potential for overlapping toxicity, data from a 
Safety Run-in Cohort will be evaluated before treating additional patients with 
advanced ovarian cancer. 
The combination of Hu5F9-G4 and avelumab in patients with platinum-resistant 
advanced ovarian cancer has the potential to address an unmet medical need by 
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2. STUDY OBJECTIVES AND ENDPOINTS 
The objectives and endpoints for the study are summarized in Table 2-1.  
Information about study assessments and procedures is provided in Section 7; 
assessment of safety is provided in Section 9; measurement of effect is provided in 
Section 10; and statistical analysis information is provided in Section 11. 
Table 2-1. 
Objectives and Endpoints 
PRIMARY 
 
OBJECTIVES 
ENDPOINTS 
Safety Run-in Cohort: 
To investigate the safety and tolerability of 
Hu5F9-G4 in combination with avelumab in 
patients with advanced solid tumors 
Ovarian Cancer Expansion Cohort: 
To confirm the safety and tolerability of this 
combination and evaluate the anti-tumor 
activity based on Response Evaluation 
Criteria in Solid Tumors (RECIST) v1.1 
(Eisenhauer 2009) in patients with 
checkpoint inhibitor-naïve ovarian cancer, 
fallopian tube cancer, and primary peritoneal 
carcinoma who have previously progressed 
within 1-6 months of receiving platinum 
chemotherapy 
AEs and DLTs graded according to 
National Cancer Institute Common 
Terminology Criteria for Adverse Events 
(NCI CTCAE) Version 4.03 (Appendix C) 
or customized AE severity grading for 
hemagglutination and microangiopathy, 
as defined in Section 6.5.1.3 (Safety 
Management Guidelines) 
Objective response as defined by the 
Investigator according to RECIST v1.1 
(Eisenhauer 2009) 
SECONDARY 
 
OBJECTIVES 
ENDPOINTS 
Safety Run-in Cohort: 
To determine a recommended dose of 
Hu5F9-G4 + avelumab in patients with solid 
tumors 
To examine the pharmacokinetic (PK) profile 
of Hu5F9-G4 in combination with avelumab 
To evaluate the immunogenicity of 
Hu5F9-G4 in combination with avelumab 
Recommended Phase 2 dose and 
schedule (RP2DS) of Hu5F9-G4 in 
combination with avelumab 
Serum concentrations of Hu5F9-G4 
collected at selected time points 
Anti-drug antibodies (ADA) to Hu5F9-G4 


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Ovarian Cancer Expansion Cohort: 
To evaluate the anti-tumor activity of 
Hu5F9-G4 in combination with avelumab in 
all patients using the Immune Response 
Evaluation Criteria in Solid Tumors 
(irRECIST; Bohnsack 2014) and, where 
applicable, the Gynecologic Cancer 
Intergroup (GCIG) response criteria 
(Rustin 2011) 
To assess additional efficacy endpoints 
including duration of response (DOR), time 
to tumor progression (TTP), progression-free 
survival (PFS), and overall survival (OS) 
To evaluate the impact of Hu5F9-G4 in 
combination with avelumab on the myeloid 
cell populations in the tumor 
microenvironment, as assessed in 
sequential tumor biopsies in patients with 
platinum-resistant ovarian cancer 
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Ovarian Cancer Expansion Cohort: 
Objective response, as defined by the 
Investigator according to irRECIST 
(Bohnsack 2014) and GCIG response 
criteria (Rustin 2011 ) 
For patients who respond, DOR will be 
evaluated. For all patients, efficacy 
endpoints will include TTP, PFS, and OS. 
lmmunohistochemical staining of myeloid 
cells in formalin-fixed, paraffin-embedded 
tissues 
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3. STUDY DESIGN 
3.1. 
Overall Study Design 
This is an open label, multicenter, Phase 1b trial investigating the combination of 
Hu5F9-G4 and avelumab in patients with solid tumors and checkpoint inhibitor-naïve 
ovarian cancer who progress within 1-6 months of receiving platinum-containing 
chemotherapy.  Checkpoint inhibitor-naïve patients are defined as those patients 
who have not been previously treated with an anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody 
(including ipilimumab, tremelimumab, or any other antibody or drug specifically 
targeting T-cell co-regulatory proteins).  The study will be conducted in 2 parts: 
Part 1–Safety Run-in Cohort:  Patients with solid tumors will be treated at 
the starting dose with Hu5F9-G4 + avelumab to examine the safety and PK of 
this study drug combination. 
Part 2–Expansion Cohort:  Patients with checkpoint inhibitor-naïve ovarian 
cancer will be treated with Hu5F9-G4 + avelumab to evaluate the safety, 
efficacy, 
effects of this study drug 
combination. 
Patients may continue treatment unless they develop unacceptable toxicities that 
cannot be clinically managed by dose or schedule modifications as outlined in 
Section 6.4, or if they have confirmed PD according to Immune-related Response 
Evaluation Criteria in Solid Tumors (irRECIST; Bohnsack 2014) as described in 
Section 10.1. 
Hu5F9-G4 and avelumab combination treatment may continue past the initial 
determination of disease progression according to irRECIST as long as the following 
criteria are met: 
• No new symptoms or worsening of previous symptoms 
• Tolerance of Hu5F9-G4 and avelumab 
• Stable ECOG performance status 
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• Treatment beyond progression will not delay an imminent intervention to 
prevent serious complications of disease progression (for example, central 
nervous system [CNS] metastases) 
If disease progression is due to brain metastasis, patients may continue avelumab 
treatment after the local treatment of the brain lesions provided that the above 
criteria are met in addition to the following and in consultation with the Medical 
Monitor: 
• Brain metastases have been treated locally and are clinically stable for at 
least 2 weeks prior to re-initiation of treatment with avelumab 
• There are no ongoing neurological symptoms that are related to the brain 
localization of the disease (sequelae that are a consequence of the treatment 
of the brain metastases are acceptable) 
• Patients must be either off steroids or on a stable or decreasing dose of ≤10 
mg daily prednisone (or equivalent) 
In addition, if disease progression is mainly due to a metastatic lesion (nodal or 
visceral) which in the opinion of the Investigator may be surgically removed or 
treated with palliative radiation therapy, patients may continue avelumab treatment 
after the local treatment of such a lesion provided that: 
• It has been at least 2 weeks (post minor surgery) or 4 weeks (post major 
surgery) and the patient has fully recovered from the surgery 
• It has been at least 2 weeks since the patient’s last dose of radiation therapy 
and any toxicity related to the radiation therapy is recovered to <Grade 2 
The decision to continue treatment should be discussed with the Medical Monitor 
and documented in the trial records. 
A radiographic assessment should be performed after 4-6 weeks of original PD to 
determine whether there has been a decrease in the tumor size, or continued PD.  
The assessment of clinical benefit should be balanced by clinical judgment as to 
whether the patient is clinically deteriorating and unlikely to receive any benefit from 
continued treatment with avelumab. 


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If the Investigator feels that the patient continues to achieve clinical benefit by 
continuing treatment, the patient should remain on the trial and continue to receive 
monitoring according to the Schedules of Assessments (Section 7). 
Patients receiving avelumab who experience a CR should strive to be treated for a 
minimum of 12 months based on clinical judgement of benefit and/or until disease 
progression or unacceptable toxicity, after confirmation of response.  In case a 
patient with a confirmed CR relapses after stopping treatment during long-term 
follow-up, but prior to the End of the Trial, 1 re-initiation of treatment is allowed at the 
discretion of the Investigator and agreement of the Medical Monitor.  To be eligible 
for re-treatment, the patient must not have experienced any toxicity that led to 
treatment discontinuation.  Patients who re-initiate treatment will stay on trial and will 
be treated and monitored according to the protocol and the “until progression” 
schedule in the Schedules of Assessments (Section 7.1).  Patients who re-initiate 
treatment will not have to undergo a second screening visit. 
in Part 2, mandatory 
pretreatment and during treatment biopsies will be collected as described in 
Section 7.3.11. 
3.2. 
Part 1 Safety Run-in Cohort:  Study Design 
The Safety Run-in Cohort (Dose Level 1) will begin by treating 6 patients.  The 
precise starting dose for Hu5F9-G4 will be a priming dose of 1 mg/kg in Week 1 
followed by 30 mg/kg weekly for 4 doses.  Starting in Cycle 2, 30 mg/kg of Hu5F9-
G4 will be given every 2 weeks.  This Hu5F9-G4 dose will be combined with the full 
single-agent dose of 800 mg of avelumab given once every 2 weeks (Table 3-1).  
The first patient in this cohort will be treated for 14 days prior to enrolling additional 
patients.  After the first 6 patients evaluable for DLT assessment have safely 
completed the Cycle 1 DLT evaluation period, and if no more than 1 DLT occurs, the 
cohort will be deemed to be safe by the Clinical Trial Steering Committee (CTSC; 
Section 11.3).  Dose Level 2 will begin by treating 6 patients with the Hu5F9-G4 
priming dose of 1 mg/kg in Week 1, followed by 45 mg/kg on Days 8,11,15, 22 and 
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29 for Cycle 1, continuing weekly in Cycle 2 on Days 1, 8, 15 and 22.  Starting in 
Cycle 3, 45 mg/kg of Hu5F9-G4 will be given every 2 weeks.  This Hu5F9-G4 dose 
will be combined with the full single-agent avelumab dose of 800 mg given every 
2 weeks (Table 3-1).  The first patient in each cohort will be treated for 14 days 
before additional patients are enrolled.  After the first 6 patients evaluable for DLT 
assessment have safely completed the Cycle 1 DLT evaluation period, the Clinical 
Trial Steering Committee (CTSC; Section 11.3) will again meet to determine the 
Part 2 dose. 
The recommended dose for patients in the Expansion Cohort must have a DLT rate 
less than 33% in at least 6 evaluable patients, and the final dose selection for Part 2 
will be made by the CTSC after all available clinical, 
and PK data 
are reviewed.  Up to an additional 6 evaluable patients may be enrolled to further 
evaluate safety and PK.  The Part 1 dose levels are described in Table 3-1.  
Dose evaluation decisions will be made by the CTSC, and DLTs for the combination 
regimen will be monitored from administration of the priming dose on Day 1 to the 
end of Cycle 1 (Day 35).  The first cycle will be 5 weeks in duration; subsequent 
cycles will last 4 weeks.  Initial tumor response assessments will be performed at 
Cycle 3 and then after every 8 weeks of treatment (every 2 cycles).  
 
  Additional assessments to 
evaluate pseudoprogression or to confirm objective responses, as required by 
irRECIST (Bohnsack 2014), may also be implemented. 
The CTSC may designate additional lower or higher dose levels to explore beyond 
those described in Table 3-1 after reviewing all available clinical data. 
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Table 3-1. 
Part 1 Hu5F9-G4 and Avelumab Dose Levels and Schedule 
Dose 
Cohort 
Drug/Dose 
(Intravenous) 
Dose Schedule 
Cycle 1 
(35 days) 
Cycle 2 
(28 days) 
Cycle 3+ 
(28 days) 
1 
Hu5F9-G4 — 1 mg/kg (priming 
dose) 
Over 3 hours (± 30 minutes) 
Day 1 
— 
— 
Hu5F9-G4 — 30 mg/kg  
Over 2 hours (± 30 minutes)  
Infusion should begin at least 
1 hour after completion of the 
avelumab infusion (on days when 
both are administered) 
Days 8, 15, 
22, 29 
Days 1 and 15 
Days 1 and 15 
Avelumab — 800 mg Q2W 
Over 1 hour (-10 to +20 minutes)  
Days 8 and 22 
Days 1 and 15 
Days 1 and 15 
2 
Hu5F9-G4 — 1 mg/kg (priming 
dose) 
Over 3 hours (± 30 minutes) 
Day 1 
— 
— 
Hu5F9-G4 — 45 mg/kg  
Over 2 hours (± 30 minutes)  
Infusion should begin at least 
1 hour after completion of the 
avelumab infusion (on days when 
both are administered) 
Days 8, 11, 
15, 22, 29 
Days 1, 8, 15, 
22 
Days 1 and 15 
Avelumab — 800 mg Q2W 
Over 1 hour (-10 to +20 minutes)  
Days 8 and 22 
Days 1 and 15 
Days 1 and 15 
The following lower dose cohort may be used if ≥2 of 6 patients in Dose Level 1 
experience DLTs: 
-1 
Hu5F9-G4 — 1 mg/kg (priming 
dose) 
Over 3 hours (± 30 minutes) 
Day 1 
— 
— 
Hu5F9-G4 — 20 mg/kg a 
Over 2 hours (± 30 minutes)  
Infusion should begin at least 
1 hour after completion of the 
avelumab infusion (on days when 
both are administered) 
Days 8, 15, 
22, 29 
Days 1 and 15 
Days 1 and 15 
Avelumab — 800 mg Q2W 
Over 1 hour (-10 to +20 minutes)  
Days 8 and 22 
Days 1 and 15 
Days 1 and 15 
The following lower dose cohort may be used if ≥2 of 6 patients in Dose Level 2 
experience DLTs: 


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Dose 
Cohort 
Drug/Dose 
(Intravenous) 
Dose Schedule 
Cycle 1 
(35 days) 
Cycle 2 
(28 days) 
Cycle 3+ 
(28 days) 
 
Hu5F9-G4 — 1 mg/kg (priming 
dose) 
Over 3 hours (± 30 minutes) 
Day 1 
— 
— 
-2 
Hu5F9-G4 — 30 mg/kg a 
Over 2 hours (± 30 minutes) 
Infusion should begin at least 
1 hour after completion of the 
avelumab infusion (on days when 
both are administered) 
Days 8, 11, 
15, 22, 29 
Days 1, 8, 15, 
22 
Days 1 and 15 
 
Avelumab — 800 mg Q2W 
Over 1 hour (-10 to +20 minutes)  
Days 8 and 22 
Days 1 and 15 
Days 1 and 15 
Abbreviations:  DLT = dose-limiting toxicity; Q2W = once every 2 weeks. 
a. If additional dose reductions are required but the patient is deemed to be benefitting from 
treatment, the dose of Hu5F9-G4 may be reduced by an additional 50%. 
 
3.2.1. 
Dose-Limiting Toxicity Assessment 
Dosing decisions will be made by the CTSC based on the first 5 weeks of treatment 
for each patient, referred to as the “Dose-Limiting Toxicity (DLT) Assessment 
Period.” 
3.2.1.1. 
Definition of DLT-evaluable Patients 
Patients in the Safety Run-in Cohort in Part 1 are considered evaluable for DLT 
assessment if they meet either of the following criteria during the DLT assessment 
period: 
• The patient experiences a DLT at any time after initiation of the first infusion 
of Hu5F9-G4 or any infusion of avelumab. 
• The patient completes the minimum safety evaluations (hematology, 
chemistry, and clinical assessments) after the administration of the study drug 
combination during the DLT observation period and receives at least 
4 complete infusions of Hu5F9-G4 and 2 complete infusions of avelumab, 
unless a DLT is observed earlier. 


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Patients who withdraw before completing the 5-week DLT assessment period for 
reasons other than a DLT, or who do not fulfill either of the criteria above, will not be 
evaluable for assessment of DLT for dose review decisions and will be replaced in 
the cohort. 
3.2.1.2. 
Definition of Dose-limiting Toxicity 
All toxicities will be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events Version 4.03 (NCI CTCAE; Appendix C). 
DLT Definition:  A DLT is defined as any Grade 3 or greater AE that is assessed as 
related to at least 1 study treatment that occurs during the 5-week DLT Assessment 
Period (DLT exceptions are defined below).  Additionally, any treatment-emergent 
adverse event (TEAE) that is, in the opinion of the CTSC, of potential clinical 
significance such that further dosing would expose patients to unacceptable risk, will 
be considered a DLT. 
DLT Exceptions:  The following are exceptions to the DLT definition and will NOT 
be considered a DLT: 
• Grade 3 anemia; however, any Grade 3 hemolytic anemia is considered a 
DLT. 
• Grade 3 indirect/unconjugated hyperbilirubinemia that resolves to ≤Grade 2 
with supportive care within 1 week and is not associated with other clinically 
significant consequences. 
However any occurrence of liver toxicity, as defined by Hy’s Law below, is 
considered a DLT: 
o The drug causes hepatocellular injury, generally shown by a higher 
incidence of 3-fold or greater elevations above the ULN of ALT or AST, 
and 
o Total Bilirubin >2×ULN, without initial findings of cholestasis (elevated 
serum alkaline phosphatase), and 
o No other reason can be found to explain the combination of increased 
ALT/AST and total bilirubin. 


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• Transient Grade 3 nausea, vomiting, diarrhea, local reactions, influenza-like 
symptoms, myalgias, fever, headache, acute pain, or skin toxicity that 
resolves to ≤Grade 2 within ≤72 hours after medical management (e.g., 
supportive care, including immunosuppressant treatment) has been initiated. 
• Grade 3 fatigue that resolves to ≤Grade 2 within 1 week on study. 
• Grade 3 Hu5F9-G4 or avelumab-related infusion reactions in the absence of 
an optimal pretreatment regimen, which is defined as acetaminophen or a 
comparable non-steroidal anti-inflammatory agent, plus an antihistamine and 
corticosteroids. 
• Grade 3 tumor lysis syndrome or electrolyte disturbances (hyperkalemia, 
hypophosphatemia, hyperuricemia, etc.) that resolves to ≤Grade 2 or baseline 
within 1 week. 
• Grade 3 lipase and/or amylase elevation without clinical or radiological 
evidence of pancreatitis. 
• Grade 3 or 4 lymphopenia or leukopenia not associated with other clinically 
significant consequences. 
• Grade 3 diarrhea or skin toxicity that resolves to Grade ≤1 in less than 7 days 
after medical management (e.g., immunosuppressant treatment) has been 
initiated. 
• Transient (≤48 hours) Grade 3 fatigue, local reactions, flu-like symptoms, 
fever, headache, nausea, emesis, and diarrhea. 
• Other single laboratory values out of normal range that have no clinical 
correlate, and resolve to Grade ≤1 or to baseline within 7 days with adequate 
medical management. 
• Tumor flare phenomenon defined as local pain, irritation, or rash localized at 
sites of known or suspected tumor. 
3.3. 
Part 2 Expansion:  Study Design 
Once the Part 1 Safety Run-in Cohort of the trial is completed and the recommended 
expansion dose(s) is determined, the CTSC will open Part 2 of the study.  Part 2 of 
the study will treat up to 20 patients with ovarian cancer at the recommended 


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dose(s) to confirm safety, PK, 
and to document preliminary 
efficacy in this population. 
In Part 2, patients may be enrolled simultaneously without an observation period 
after the first patient starts treatment.  Based on review of ongoing dosing data, the 
CTSC may recommend testing of multiple doses in Part 2. 
Mandatory tumor biopsies will be collected, where medically feasible, from all 
patients during the Screening Period prior to first dose and at Cycle 3, Day 1 
(± 2 weeks).  
  
Efficacy will be evaluated using RECIST v1.1 (primary endpoint; Eisenhauer 2009) 
and irRECIST (secondary endpoint; Bohnsack 2014).  Study treatment with study 
drug may be continued until an unacceptable drug-related toxicity occurs or until 
disease progression according to irRECIST.  Patients who experience initial PD may 
remain on study until they are deemed to have confirmed progressive disease 
according to irRECIST, provided all of the following conditions are met: 
• No new symptoms or worsening of previous symptoms 
• Tolerance of Hu5F9-G4 and avelumab 
• Stable ECOG performance status 
• Treatment beyond progression will not delay an imminent intervention to 
prevent serious complications of disease progression (for example, CNS 
metastases) 
Patients who discontinue from treatment for reasons other than confirmed PD will 
undergo scheduled tumor assessments until documentation of PD or initiation of a 
new line of anti-cancer therapy, whichever occurs first. 
3.4. 
Number of Sites 
Approximately 5 to 8 sites located in the US will participate in this trial.  Additional 
sites may be included based on enrollment and study timelines. 
3.5. 
Estimated Study Duration 
It is anticipated that this study will take approximately 20 months to complete. 
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Patient participation will include Screening, Treatment, and Follow-Up.  Screening 
will last up to 30 days before first dose of study drug, during which time the patient’s 
eligibility and baseline characteristics will be determined.  Treatment with study drug 
may be continued until an unacceptable drug-related toxicity occurs or until disease 
progression.  After treatment, patients will be observed for survival for up to 5 years 
from date of enrollment, or until death, withdrawal of consent, or the end of the 
study, whichever occurs first.  Patients who discontinue from treatment for reasons 
other than confirmed PD will undergo scheduled tumor assessments until 
documentation of PD or initiation of a new line of anti-cancer therapy, whichever 
occurs first. 
Final study analysis may be implemented at the discretion of the CTSC once all 
Part 2 patients enrolled have come off study or have had at least 1 tumor efficacy 
assessment to allow for timely reporting of study results.  Treatment or long-term 
follow-up (LTFU) and Survival Follow-up will continue and be reported in an 
addendum to the Clinical Study Report. 
4. PATIENT SELECTION AND ENROLLMENT 
Only individuals who fulfill all inclusion criteria and none of the exclusion criteria may 
be enrolled into the trial, with no exceptions.  The Investigator will ensure that the 
patient or the patient’s legal representative has provided written informed consent (in 
accordance with the procedure described in Section 12.4) before performing any trial 
assessments that are not part of the patient’s routine medical care. 
4.1. 
Inclusion Criteria 
1. Meets the criteria for the appropriate cohort: 
• Part 1 Safety Run-in Cohort:  Pathologically confirmed advanced solid 
tumors for which no further conventional therapy is suitable for the 
patient and for which there is no curative therapy available.  Prior 
checkpoint inhibitor treatment therapy is permitted. 
• Part 2 Ovarian Cancer Expansion Cohort:  Histologically or 
cytologically confirmed, epithelial ovarian, fallopian tube, or peritoneal 


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cancer patients who are checkpoint inhibitor-naïve.  All histological 
subtypes of ovarian epithelial tumors are allowed.  Patients must have 
had, at any point, documented PD as determined by Gynecologic 
Cancer InterGroup (GCIG) criteria (Rustin 2011) within 1-6 months 
after the last day of receiving the last platinum-containing 
chemotherapy.  Patients must have received at least 1 prior line of a 
platinum-based chemotherapy regimen to be eligible.  Patients may 
have received any additional number of prior systemic therapies for 
metastatic disease including PARP inhibitors. 
2. Part 2 Ovarian Cancer Expansion Cohort:  Disease must be measurable or 
assessable for response according to RECIST v1.1 (primary endpoint; 
Eisenhauer 2009) and irRECIST (secondary endpoint; Bohnsack 2014). 
3. Age ≥18 years. 
4. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 2 
(Appendix D). 
5. Laboratory measurements, blood counts: 
• Hemoglobin ≥9.5 g/dL (RBC transfusions are permitted during the 
Screening Period and prior to enrollment to meet the hemoglobin 
inclusion criterion.) 
• Absolute neutrophil count (ANC) ≥1.5 × 109/L. 
• Platelets ≥100 × 109/L. 
6. Laboratory measurements, hepatic function: 
• AST/ ALT ≤3 × upper limit of normal (ULN), or ≤5 × ULN for patients 
with intrahepatic liver metastases. 
• Bilirubin ≤1.5 × ULN or ≤3.0 × ULN and primarily unconjugated if 
patient has a documented history of Gilbert’s syndrome or a genetic 
equivalent. 
7. Laboratory measurements, renal function: 


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• Serum creatinine ≤1.5× ULN or if elevated, a calculated glomerular 
filtration rate (GFR) >30 mL/min/1.73 m2. 
8. For patients in Part 1 
 
 a formalin-fixed paraffin-embedded (FFPE) block 
containing tumor tissue not older than 6 months from the time of screening or 
a minimum of 10 (preferably 25) unstained tumor slides (cut within 1 week) 
suitable for PD-L1 expression assessment will be collected.  The tissue 
should be collected from a non-irradiated area and there should be at least 
1 measurable lesion remaining for tumor response assessment. 
9. Negative urine or serum pregnancy test within 30 days before enrollment and 
within 72 hours before the first administration of study drug for female patients 
of childbearing potential. 
10. Female patients of childbearing potential must be willing to use 1 highly 
effective method of contraception during the study and continue for 4 months 
after the last dose of Hu5F9-G4 and 1 month after the last dose of avelumab 
(Section 4.6.1). 
11. Male patients who are sexually active with a woman of childbearing potential 
and who have not had vasectomies must be willing to use a highly effective 
barrier method of contraception during the study and for 4 months after the 
last dose of Hu5F9-G4 and 1 month after the last dose of avelumab 
(Section 4.6.2). 
12. Patient has provided informed consent. 
13. Must be willing and able to comply with the clinic visits and procedures 
outlined in the study protocol. 
14. For Part 2 (Ovarian Cancer Expansion Cohort) only:  Willing to consent to 
1 mandatory pre-treatment and 1 during-treatment tumor biopsy unless not 
medically feasible as determined by the Investigator (reasons include, but are 
not limited to, lack of accessible tumor tissue to biopsy and patient safety 
issues). 
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4.2. 
Exclusion Criteria 
1. Patients with symptomatic or untreated CNS metastases.  (Patients with 
stable, asymptomatic, treated CNS lesions who are off of corticosteroids and 
radiation therapy for at least 3 weeks are permitted.) 
2. Prior or concurrent anti-cancer therapy including chemotherapy, hormonal 
therapy, or investigational agents within 2 weeks or within at least 4 half-lives 
prior to Hu5F9-G4 dosing (up to a maximum of 4 weeks), whichever is longer.  
In all situations, the maximum required washout period will not exceed 
4 weeks prior to the day of first treatment with Hu5F9-G4. 
The following are not criteria for exclusion: 
• Localized non-CNS radiotherapy (>14 days before enrollment) 
• Previous hormonal therapy with luteinizing-hormone releasing 
hormone (LHRH) agonists for prostate cancer 
• Low dose steroids (oral prednisone or equivalent ≤10 mg per day) 
• Treatment with bisphosphonates and receptor activator of nuclear 
factor kappa-B ligand (RANKL) inhibitors 
3. For Part 2 Ovarian Cancer Expansion Cohort only:  Prior therapy with an 
anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody 
(including ipilimumab, tremelimumab, or any other antibody or drug 
specifically targeting T-cell co-regulatory proteins). 
4. Prior treatment with CD47 or SIRPα targeting agents. 
5. Known active or chronic hepatitis B or C infection or human 
immunodeficiency virus (HIV). 
6. RBC transfusion dependence, defined as requiring more than 2 units of RBCs 
transfused during the 4-week period prior to Screening.  RBC transfusions are 
permitted during the Screening Period and prior to enrollment to meet the 
hemoglobin inclusion criteria. 
7. Prior organ transplantation, including allogeneic stem-cell transplantation, 
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8. Prior hemolytic anemia or Evans Syndrome in the last 3 months. 
9. Hypersensitivity to the active substance or to any of the other excipients of 
Hu5F9-G4 or avelumab, including known severe hypersensitivity reactions to 
monoclonal antibodies (NCI CTCAE v4.03, Grade ≥3; Appendix C). 
10. Significant medical diseases or conditions that would substantially worsen the 
risk-benefit ratio of participating in the study.  This includes, but is not limited 
to, acute myocardial infarction within the last 6 months, unstable angina, 
significant acute or chronic infections, severely immunocompromised state, 
and congestive heart failure (New York Heart Association (NYHA) Class 
II-IV). 
11. Known history of inflammatory colitis, inflammatory bowel disease, 
pneumonitis, or pulmonary fibrosis. 
12. History of uncontrolled intercurrent illness including but not limited to: 
• Hypertension uncontrolled by standard therapies (not stabilized to 
150/90 mmHg or lower) 
• Uncontrolled active infection 
• Uncontrolled diabetes (e.g., hemoglobin A1c ≥8%) 
• Uncontrolled asthma 
13. Radiotherapy within 14 days prior to enrollment. 
14. For Part 2 Expansion Cohort only:  Previous malignant disease (other than 
the tumor disease for this trial and with the exception of adequately treated 
non-melanoma skin cancers, and carcinoma in situ of skin, bladder, cervix, 
colon/rectum, or breast) unless in a stable remission for at least 2 years prior 
to study entry. 
15. History of psychiatric illness or substance abuse likely to interfere with ability 
to comply with protocol requirements or give informed consent. 
16. Patient or designees are or become incapable of providing legal informed 
consent. 


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17. Current use of the following medications at the time of enrollment: 
• Immunotherapy or immunosuppressive drugs (e.g., chemotherapy or 
systemic corticosteroids) EXCEPT for the following:  a. intranasal, 
inhaled, topical steroids, or local steroid injection (e.g., intra-articular 
injection); b. systemic corticosteroids at physiologic doses ≤10 mg/day 
of prednisone or equivalent; c. steroids as premedication for 
hypersensitivity reactions (e.g., CT scan premedication). 
• Growth factors (granulocyte colony stimulating factor or granulocyte 
macrophage colony stimulating factor) EXCEPT for erythropoietin and 
darbepoetin alpha. 
• Herbal remedies with immunostimulating properties (e.g., mistletoe 
extract) or known to potentially interfere with major organ function 
(e.g., hypericin). 
18. Administration of a live vaccine within 28 days prior to enrollment. 
19. Pregnancy or active breast feeding. 
20. Active autoimmune disease or treatment with systemic immunosuppression 
for organ transplantation. 
The following are not criteria for exclusion: 
• Type I diabetes mellitus 
• Vitiligo 
• Mild-to-moderate psoriasis 
• Clinically stable hypo- or hyperthyroid disease not requiring 
immunosuppressive treatment 
21.  Positive IgG component of the direct antiglobulin test (DAT). 
4.3. 
Patient Screening 
All patients who enter the Screening period for the study, which starts when the 
patient signs the informed consent form, will receive a unique patient identification 
number before any study procedures are performed.  This number is used to identify 


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the patient throughout the clinical trial and must be used on all study documentation 
related to that patient, including if a patient is rescreened. 
Screening laboratory assessments may be tested repeatedly within the 30 days prior 
to the first dose of study treatment.  Patients who initially failed screening may 
repeat the screening process if the patient’s medical condition has changed. 
All patients who provide informed consent must be registered in the Interactive 
Response Technology (IRT) system, including any screen failures. 
A patient is defined as enrolled in the study once all eligibility criteria have been 
satisfied and the patient is assigned to a cohort or study arm assignment.  After 
signing the informed consent, eligible patients are expected to receive the first dose 
of Hu5F9-G4 (Cycle 1, Day 1) within 30 days. 
4.4. 
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 Institutional Review Board (IRB)/Research 
Ethics Committee (REC) approved informed consent form (ICF) prior to participation 
in any study specific procedure.  Data from assessments performed as part of 
standard of care prior to ICF signature may be used if they are within the required 
Screening Period.  The participant must receive a copy of the signed and dated 
consent documents.  A signed copy (in paper or electronic format) of the consent 
documents must be retained in the medical record or research file. 
4.5. 
Registration Process 
Patient will be assigned the patient number at the time of consent.  The site will 
register the patient through IRT. 
Prior to being assigned to a dose cohort or treatment arm, patients must have 
signed the ICF and satisfied all of the study eligibility criteria.  The Investigator will 


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determine the eligibility of the patient.  Once patients have been assigned to a dose 
cohort or treatment arm, they will be considered enrolled. 
4.6. 
Contraception Requirements 
4.6.1. 
Female Patients 
Female patients of childbearing potential who have a negative serum or urine 
pregnancy test before enrollment must agree to use 1 of the following highly 
effective forms of contraception (defined as methods that can achieve a failure rate 
of less than 1% per year when used consistently and correctly): 
• Bilateral tubal occlusion 
• Vasectomized partner 
• Intra-uterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Combined hormonal contraception (estrogen- and progestogen-containing) 
associated with inhibition of ovulation (oral, intravaginal, transdermal) 
• Progestogen-only hormonal contraception associated with inhibition of 
ovulation (oral, injectable, implantable) 
• Abstinence 
Defined as:  refraining from heterosexual intercourse for the entire period of 
risk associated with the study treatments.  Periodic abstinence is not 
acceptable (calendar, symptothermal, post-ovulation methods), nor is the 
withdrawal method (coitus interruptus), spermicides only, and lactational 
amenorrhea method.  The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the clinical trial and the preferred and 
usual lifestyle of the patient. 
Contraception must be effective at the first administration of any of the study drugs 
(Hu5F9-G4 or avelumab), throughout the trial, and for 4 months after the last dose of 
Hu5F9-G4 or 1 month after the last dose of avelumab, whichever occurs latest. 


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4.6.2. 
Male Patients 
A man who is sexually active with a woman of childbearing potential and has not had 
a vasectomy must agree to use a highly effective barrier method of birth control 
(e.g., either condom with spermicidal foam/gel/film/cream/suppository or partner with 
occlusive cap [diaphragm or cervical/vault caps] with spermicidal 
foam/gel/film/cream/suppository) during the study, and all men must also agree not 
donate sperm for the duration of the study treatment and for 4 months after the last 
dose of Hu5F9-G4 or 1 month after the last dose of avelumab, whichever occurs 
latest. 
Contraception must be effective at the first administration of any of the study drugs 
(Hu5F9-G4 or avelumab), throughout the trial, and for 4 months after the last dose of 
Hu5F9-G4 or 1 month after the last dose of avelumab, whichever occurs latest. 
It should be explained to the patient that if his partner is pregnant or breastfeeding 
when he is enrolled on the trial, the patient should use barrier method contraception 
(condom plus spermicidal gel) to prevent the unborn fetus or the baby being 
exposed to investigational product. 
5. STUDY DRUG INFORMATION 
Refer to the Pharmacy Manual for detailed instructions for Hu5F9-G4 and avelumab 
preparation and handling. 
5.1. 
Physical Description of Study Drug 
5.1.1. 
Hu5F9-G4 
The active pharmaceutical ingredient (API) is Hu5F9-G4, a humanized IgG4 
monoclonal antibody of the IgG4 kappa isotype containing a Ser-Pro (S-P) 
substitution in the hinge region (position 228) of the heavy chain to reduce Fab arm 
exchange.  It comprises a disulfide-linked glycosylated tetramer, consisting of two 
identical 444 amino acid heavy gamma chains and two identical 219 amino acid 
kappa light chains.  Hu5F9-G4 targets the human CD47 antigen.  Hu5F9-G4 drug 
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Hu5F9-G4 active API is manufactured under current Good Manufacturing Practices. 
Hu5F9-G4 is supplied in single-use, 10-mL vials containing 200 mg of the antibody 
in a formulation of 10 mM sodium acetate, 5% (w/v) sorbitol, 0.01% (w/v) 
polysorbate 20, at pH of 5.0. 
The labeling complies with the requirements of the applicable regulatory agencies. 
Additional details about Hu5F9-G4 are provided in the Pharmacy Manual. 
5.1.2. 
Avelumab 
Avelumab (BAVENCIO®) is a programmed death ligand-1 (PD-L1) blocking 
antibody.  Avelumab is a human IgG1 lambda monoclonal antibody that has a 
molecular weight of approximately 147 kDa. 
BAVENCIO (avelumab) Injection for intravenous use is a sterile, clear, colorless to 
slightly yellow concentrate for solution for infusion.  It is presented at a concentration 
of 20 mg/mL in single-use glass vials closed with a rubber stopper and sealed with 
an aluminum polypropylene flip-off seal.  Each single-dose vial contains 200 mg 
avelumab in 10 mL (20 mg/mL).  Each mL contains 20 mg avelumab, D-mannitol 
(51 mg), glacial acetic acid (0.6 mg), polysorbate 20 (0.5 mg), sodium hydroxide 
(0.3 mg), and Water for Injection.  The pH range of the solution is 5.0 to 5.6.  
The labeling complies with the requirements of the applicable regulatory agencies.  
Additional details about avelumab are provided in Appendix B. 
6. TREATMENT ADMINISTRATION 
6.1. 
Study Drug Administration Guidance:  Hu5F9-G4 and Avelumab 
6.1.1. 
Dosing 
The Hu5F9-G4 and avelumab dose levels and schedules are outlined above in 
Table 3-1 for Part 1, and also in the Study Schemas for Part 1 and Part 2.  The dose 
of Hu5F9-G4 will be calculated based on the weight of the patient measured within 
72 hours prior to enrollment and remains constant throughout the study, unless there 
is a >10% change in weight from baseline.  Modifications to the study drug doses 


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administered should be made for a >10% change in body weight and for dose 
modifications as described in Section 6.4.  Dose modifications for changes in body 
weight <10% may be made according to local institutional guidelines. 
Avelumab will be given at a fixed dose of 800 mg every 2 weeks for all patients. 
6.1.2. 
Premedication 
Hu5F9-G4 
Premedication with oral acetaminophen 650–1000 mg and oral or intravenous 
diphenhydramine 25 mg, or comparable regimen, is required before administration 
of the first 2 doses of Hu5F9-G4 (inclusive of the priming dose).  If less than 4 hours 
has elapsed since a prior dose of acetaminophen has been given, for example, as a 
premedication for avelumab, the dose of acetaminophen premedication for Hu5F9-
G4 may be omitted.  Premedication may be given at any time on the day(s) of 
dosing, up to 15 minutes prior to dosing.  Premedication for subsequent Hu5F9-G4 
treatments may be continued based upon the treating physician’s clinical judgement 
and the presence/severity of prior infusion-related reactions.  Premedications used 
to manage infusion-related reactions are described in Section 6.5.1.1. 
Avelumab 
Premedication with an antihistamine and with acetaminophen (for example, 25 to 
50 mg intravenous or oral diphenhydramine and 500 to 650 mg oral acetaminophen) 
approximately 30 to 60 minutes prior to the first 4 doses of avelumab is mandatory.  
Premedication should be administered for subsequent avelumab doses based on 
clinical judgment and presence/severity of prior infusion-related reactions.  This 
regimen may be modified based on local treatment standards and guidelines as 
appropriate.  However, the prophylactic use of systemic corticosteroids is not 
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6.1.3. 
Timing of Dosing 
In both study parts, Cycle 1 will be 5 weeks in duration and Cycles 2+ will be 
4 weeks. The Hu5F9-G4 and avelumab dose levels and schedules are outlined 
above in Table 3-1, and in the Study Schemas provided above for Part 1 and Part 2. 
On days when both study drugs are being administered, Hu5F9-G4 will be 
administered at least 1–2 hours after the completion of avelumab infusion. 
6.1.4. 
Patient Monitoring After Infusion 
Following the first 4 avelumab infusions, patients must be observed for 1 hour after 
the completion of the infusion for potential infusion-related reactions. 
All patients should be monitored for 1 hour after the completion of each Hu5F9-G4 
weekly infusion for the first 5 weeks.  Post-infusion monitoring should begin after 
Hu5F9-G4 is given.  Post-infusion monitoring is not required for doses after Cycle 1.  
Patients who experience any study drug-related AEs during the observation period 
should be further monitored, as clinically appropriate. 
Immediate access to an Intensive Care Unit (ICU) or equivalent environment and 
appropriate medical therapy (including epinephrine, corticosteroids, 
IV antihistamines, bronchodilators, and oxygen) must be available for use in the 
treatment of infusion-related reactions. Infusion of avelumab will be stopped if the 
patient experiences Grade ≥2 infusion-related, allergic, or anaphylactoid reactions. 
6.1.5. 
Repriming 
The following list describes the requirements for Hu5F9-G4 repriming. 
• Patients who experience an interruption of >2 weeks after receiving only the 
priming dose (1 mg/kg) must be “reprimed” by receiving the Hu5F9-G4 
priming dose of 1 mg/kg IV over 3 hours (±30 minutes) and 3 subsequent 
weekly maintenance doses prior to starting the twice weekly dosing schedule. 
• Patients who experience an interruption of >4 weeks after receiving at least 
1 dose (i.e., 30 mg/kg, 45 mg/kg) must be “reprimed” by receiving the 


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Hu5F9-G4 priming dose of 1 mg/kg IV over 3 hours (±30 minutes) and 
3 weekly maintenance doses prior to starting the twice weekly dosing 
schedule.  
• Avelumab must be administered as regularly scheduled (e.g. Hu5F9-G4 
repriming doses may be administered on the same day as avelumab is given 
and administration of avelumab every 2 weeks should be maintained.) 
• Premedication is required for the repriming dose and the first weekly 
maintenance dose (Section 6.1.2). 
On the day that patients receive their repriming dose, a predose ADA sample is to 
be collected. 
For patients who are reprimed, the following assessments are to be performed at the 
supplemental weekly visits (e.g., Day 8, Day 22): 
• CBC with differential, platelets, reticulocytes 
• Peripheral blood smear 
• Serum chemistry 
• Haptoglobin, D-dimer, thrombin, fibrinogen 
• PT/INR, aPTT 
• Vital signs 
• Physical examination 
• Adverse events 
• Concomitant medications 
 
6.2. 
Hu5F9-G4 Preparation and Administration 
6.2.1. 
Preparation 
Patients should be premedicated in accordance with Section 6.1.2.  Hu5F9-G4 
should be prepared as outlined in the Pharmacy Manual. 


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6.2.2. 
Administration 
6.2.2.1. 
Priming Dose 
All patients will receive a priming dose of 1 mg/kg Hu5F9-G4 on Day 1 of Cycle 1.  
The duration of the infusion of the priming dose will be 3 hours (±30 minutes).  
The priming dose will be administered in Cycle 1 only.  Repriming doses are 
required for patients who experience dose interruptions or treatment delays of 
>4 weeks.  Details are provided in Section 6.4.2.3. 
6.2.2.2. 
Maintenance Dose 
The priming dose of Hu5F9-G4 will be followed by the maintenance doses of 
Hu5F9-G4. 
In Part 1 of the study, 2 doses and 2 dosing schedules are planned.  Additional dose 
levels and schedules may be evaluated based on emerging study data and after 
CTSC review. 
In Dose Level 1, Hu5F9-G4 maintenance doses will be administered at a dose of 
30 mg/kg as an IV infusion over 2 hours (±30 minutes) Cycle 1 doses will be 
administered on Days 8, 15, 22, and 29, while doses in Cycles 2+ will be 
administered on Days 1 and 15. 
In Dose Cohort 2, Hu5F9-G4 will be administered at a dose of 45 mg/kg as an 
IV infusion over 2 hours (±30 minutes).  Cycle 1 doses will be administered on Days 
8, 11, 15, 22, and 29.  Cycle 2 doses will be administered on Days 1, 8, 15, and 22.  
Doses in Cycles 3+ will be administered on Days 1 and 15. 
In Part 2 of the study, Hu5F9-G4 will be dosed based on the dose and schedule 
selection that will be made by the CTSC after all available clinical, 
 and PK data are reviewed from Part 1. 
On days when both study drugs are given, Hu5F9-G4 will be administered at least 
1 hour after the completion of the avelumab infusion.  Proposed doses of study drug 
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to be administered are outlined above in Table 3-1, and in the 
Study Design Schemas provided above for Part 1 and Part 2. 
Modifications to the infusion rate due to infusion-related reactions are described in 
Section 6.5.2.  Patients will receive Hu5F9-G4 Q2W until the criteria in Section 8 are 
met. 
6.3. 
Avelumab Preparation and Administration 
6.3.1. 
Preparation 
Patients should be premedicated in accordance with Section 6.1.2.  Avelumab 
should be prepared as outlined in the Pharmacy Manual. 
6.3.2. 
Administration 
No priming dose is required for avelumab.  In Part 1 of the study, avelumab will be 
administered intravenously at a fixed dose of 800 mg over 1 hour (˗10 to 
+20 minutes).  Because of the different cycle lengths (due to the priming dose of 
Hu5F9-G4) Cycle 1 doses will be administered on Days 8 and 22, while doses in 
Cycles 2+ will be administered on Days 1 and 15.  Administration should be through 
an IV line containing a sterile, non-pyrogenic, low protein binding in-line filter 
(pore size of 0.2 micron).  Drugs should not be co-administered through the same 
IV line.  In Part 2 of the study avelumab will be fixed at 800 mg. 
On days when both study drugs are given, Hu5F9-G4 will be administered at least 
1 hour after the completion of the avelumab infusion.  Proposed doses of study drug 
to be administered are outlined above in Table 3-1, and in the Study Schemas 
provided for Part 1 and Part 2. 
Modifications to the infusion rate due to infusion-related reactions are described in 
Section 6.5.2.  Patients will receive avelumab once every 2 weeks until the criteria in 
Section 8 are met. 


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6.4. 
Dose Delays, Dose Modifications, and Treatment Termination 
6.4.1. 
Treatment Termination:  Hu5F9-G4 and Avelumab 
Because of the possibility of an initial increase in tumor burden caused by immune 
cell infiltration in the setting of a T-cell response (termed pseudoprogression) with 
immunotherapy treatment, radiographic progression defined as unconfirmed 
progressive disease according to irRECIST (irPD; Bohnsack 2014) may not be 
indicative of true PD.  Patients who meet criteria for unconfirmed irPD while 
receiving treatment will be permitted to continue treatment if they meet all of the 
criteria provided in Section 3.1.  If the treating physician and Sponsor agree that it is 
in the best interest of the patient to continue treatment with either Hu5F9-G4 or 
avelumab alone, the patient may continue to participate in the study provided that 
other protocol stipulations are met. 
Treatment termination is defined as permanent discontinuation of both study drugs. 
6.4.2. 
Hu5F9-G4 
6.4.2.1. 
Dose Modifications:  Study Part 1 
Proposed doses of study drug to be administered are outlined above in Table 3-1.  
Dose modifications or dose delays should be implemented for any AEs that meet the 
DLT criteria, as defined in Section 3.2.1.2 (refer to Part 1 in Table 6-1).  Hu5F9-G4 
may be re-introduced at a lower dose level if the AE has recovered to Grade 0-1, or 
to baseline, within 4 weeks.  Data from patients who restart dosing after the recovery 
period will not contribute to the MTD evaluation at the lower dose level.  Treatment 
delays of more than 4 weeks (such as for an unrelated medical condition with 
expected recovery) must be approved by the CTSC.  Patients with an interruption or 
treatment delay of longer than 2 weeks after receiving only the priming dose 
(1 mg/kg) or >4 weeks after receiving at least 1 maintenance dose (e.g., 30 mg/kg, 
45 mg/kg) must be “reprimed” by receiving the priming dose of 1 mg/kg IV over 
3 hours (±30 minutes) and 3 subsequent weekly maintenance doses following the 


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repriming dose prior to resuming the twice-weekly dosing schedule 
(Section 6.1.5, Repriming). 
6.4.2.2. 
Dose Modifications:  Study Part 2 
Patients who experience a Grade 3 or 4 study drug-related AE (that matches the 
criteria for a DLT, as defined in Part 1) should have their Hu5F9-G4 doses reduced 
in subsequent treatments to the next lower dose level, or as suggested in discussion 
with the Medical Monitor.  Table 6-1 outlines the toxicities requiring an Hu5F9-G4 
dose reduction.  If the Grade 3 or 4 AE recurs after dose reduction, study drug 
should be discontinued, unless the treating physician and Sponsor agree that the 
patient is clinically benefitting.  If additional dose reductions are required but the 
patient is deemed to be benefitting from treatment, the dose of Hu5F9-G4 may be 
reduced by an additional 50%.  Refer to Table 3-1 for dose modification level -1, that 
should be made based on the proposed initial assigned dose of Hu5F9-G4 [Dose 
Level 1] in Part 2.) 
Table 6-1. 
Hu5F9-G4-related Toxicities Requiring Dose Reduction 
Toxicity 
Specific Finding 
Requiring Action 
Recommended Action Taken with 
Hu5F9-G4 
DLT in 
Study Part 1  
A DLT is defined as:  any 
Grade 3 or greater AE 
assessed as related to 
study treatment during 
the 5-week DLT 
assessment period (refer 
to exceptions listed in 
Section 3.2.1.2). 
Actions taken for DLTs observed in Part 
1 should be in accordance with 
Section 3.2 and Section 6.4.2.1. 
Any AE assessed 
as related to Hu5F9-
G4 
Grade 3 or greater 
• First occurrence:  reduce by 1 dose 
level. 
• If recurs after 1 dose level reduction:  
permanently discontinue unless 
patient is clinically benefitting. 
• Second occurrence:  second dose 
level reduction. 
• After 2 dose level reductions:  
permanently discontinue. 
Anemia  
Grade 3 hemolytic 
anemia that is medically 
• First occurrence:  Reduce by 1 dose 
level. 


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Toxicity 
Specific Finding 
Requiring Action 
Recommended Action Taken with 
Hu5F9-G4 
significant (requiring 
hospitalization or 
prolongation of existing 
hospitalization, disabling, 
or limiting self-care 
ADLs) 
• If recurs after 1 dose level reduction:  
permanently discontinue unless 
patient is clinically benefitting. 
• Second occurrence:  second dose 
level reduction. 
• After 2 dose level reductions: 
permanently discontinue. 
Grade 4  
First occurrence:  permanently 
discontinue unless patient is clinically 
benefitting. 
Hyperbilirubinemia 
Grade 3 indirect/ 
unconjugated 
hyperbilirubinemia that 
does not resolve to 
≤Grade 2 with supportive 
care within 1 week and is 
associated with other 
clinically significant 
consequences 
• First occurrence:  reduce by 1 dose 
level. 
• If recurs after 1 dose level reduction:  
permanently discontinue unless 
patient is clinically benefitting. 
• Second occurrence:  second dose 
level reduction. 
• After 2 dose level reductions:  
permanently discontinue. 
  
Grade 4 
First occurrence:  permanently 
discontinue unless patient is clinically 
benefitting. 
Electrolytes 
Grade 3 isolated 
abnormality that does not 
resolve to ≤Grade 2 with 
supportive care within 
1 week and is associated 
with other clinically 
significant consequences 
• First occurrence:  reduce by 1 dose 
level. 
• If recurs after 1 dose level reduction:  
permanently discontinue unless 
patient is clinically benefitting. 
• Second occurrence:  second dose 
level reduction. 
• After 2 dose level reductions:  
permanently discontinue. 
Grade 4 
First occurrence:  permanently 
discontinue unless patient is clinically 
benefitting. 
ALT, AST, or 
alkaline 
phosphatase 
Grade 3 elevation that 
does not resolve to 
≤Grade 2 with supportive 
care within 1 week and is 
associated with other 
clinically significant 
consequences 
• First occurrence:  reduce by 1 dose 
level. 
• If recurs after 1 dose level reduction:  
permanently discontinue unless 
patient is clinically benefitting. 
• Second occurrence:  second dose 
level reduction. 
• After 2 dose level reductions:  


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Toxicity 
Specific Finding 
Requiring Action 
Recommended Action Taken with 
Hu5F9-G4 
permanently discontinue. 
 
If the finding is consistent 
with the definition of Hy’s 
Law (Section 3.2.1.2) 
Permanently discontinue treatment. 
  
Grade 4 
First occurrence:  permanently 
discontinue unless patient is clinically 
benefitting. 
Nausea, vomiting, 
or diarrhea 
Grade 3 that does not 
resolve to ≤Grade 2 with 
supportive care within 
72 hours  
• First occurrence:  reduce by 1 dose 
level. 
• If recurs after 1 dose level reduction:  
permanently discontinue unless 
patient is clinically benefitting. 
• Second occurrence:  second dose 
level reduction. 
• After 2 dose level reductions:  
permanently discontinue. 
Grade 4 
First occurrence:  permanently 
discontinue unless patient is clinically 
benefitting. 
Fatigue 
Grade 3 that does not 
resolve to ≤Grade 2 with 
supportive care within 2 
weeks on study 
• First occurrence:  reduce by 1 dose 
level. 
• If recurs after 1 dose level reduction:  
permanently discontinue unless 
patient is clinically benefitting. 
• Second occurrence:  second dose 
level reduction. 
• After 2 dose level reductions:  
permanently discontinue. 
Grade 4 
First occurrence:  permanently 
discontinue unless patient is clinically 
benefitting. 
Hu5F9-G4 
infusion-related 
reactions 
Grade 3 in the presence 
of an optimal 
pretreatment regimen 
(defined as 
acetaminophen or a 
comparable non-steroidal 
anti-inflammatory agent, 
plus an antihistamine and 
corticosteroids) 
• First occurrence:  reduce by 1 dose 
level. 
• If recurs after 1 dose level reduction:  
permanently discontinue unless 
patient is clinically benefitting. 
• Second occurrence:  second dose 
level reduction. 
• After 2 dose level reductions:  
permanently discontinue. 
Grade 4 
First occurrence:   


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Toxicity 
Specific Finding 
Requiring Action 
Recommended Action Taken with 
Hu5F9-G4 
If priming dose, permanently 
discontinue. 
For subsequent dose, permanently 
discontinue unless patient is clinically 
benefitting. 
Tumor lysis or 
electrolyte 
disturbances 
Grade 3 tumor lysis or 
electrolyte disturbances 
(hyperkalemia, 
hypophosphatemia, 
hyperuricemia, etc.) that 
does not resolve to 
≤Grade 2 or baseline 
within 1 week 
• First occurrence:  reduce by 1 dose 
level. 
• If recurs after 1 dose level reduction:  
permanently discontinue unless 
patient is clinically benefitting. 
• Second occurrence:  second dose 
level reduction. 
• After 2 dose level reductions:  
permanently discontinue. 
Grade 4 
First occurrence:  permanently 
discontinue unless patient is clinically 
benefitting. 
Abbreviations:  1st = first; 2nd = second; AE = adverse event; ADL = activities of daily living; 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; DLT = dose-limiting toxicity. 
6.4.2.3. 
Interruption of Hu5F9-G4 Treatment 
For patients who experience dose interruptions, instructions for repriming are 
provided in Section 6.1.5. 
6.4.3. 
Avelumab 
6.4.3.1. 
Dose Modifications 
Recommended dose modifications of avelumab for adverse reactions are provided 
in the Avelumab PI, provided in Appendix B.  Detailed information regarding clinical 
and laboratory monitoring guidelines for early detection of adverse reactions to 
avelumab and recommended management (immunosuppressant treatment 
guidelines) are described in the Warnings and Precautions (5) section of the 
Avelumab PI. 


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6.5. 
Safety Management Guidelines 
6.5.1. 
Hu5F9-G4-related Events 
6.5.1.1. 
Management of Infusion-related Reactions 
Infusion-related reactions are defined by the NCI CTCAE (under the category 
“General disorders and administration site conditions”) as “a disorder characterized 
by adverse reaction to the infusion of pharmacological or biological substances.”  
For the purposes of this study, the time frame for infusion-related reaction 
assessment is the 24-hour period beginning from the start of the infusion.  
Recommendations for the management of infusion-related reactions are provided 
below. 
• For Grade 1 infusion-related reactions, described as mild transient reaction, 
infusion interruption is not indicated, intervention is not indicated: 
o Remain at bedside and monitor patient until recovery from symptoms. 
• For Grade 2 infusion-related reactions, infusion interruption is indicated, but 
patient responds promptly to symptomatic treatment (e.g., antihistamines, 
non-steroidal anti-inflammatory drugs, narcotics, corticosteroids, IV fluids); 
and prophylactic medications are indicated for ≤24 hours: 
o Stop the Hu5F9-G4 infusion, begin an IV infusion of normal saline, and 
consider treating the patient with diphenhydramine 50 mg IV (or 
equivalent) and/or 500–750 mg oral acetaminophen. 
o Remain at bedside and monitor patient until resolution of symptoms. 
o Corticosteroid therapy may also be given at the discretion of the 
Investigator. 
o If the infusion is interrupted, wait until symptoms resolve, then restart the 
infusion at 50% of the original infusion rate. 
o If no further complications occur after 1 hour (± 10 minutes), the rate may 
be increased to 100% of the original infusion rate.  Monitor the patient 
closely. 
o If symptoms recur, stop infusion and disconnect patient from the infusion 
apparatus.  No further Hu5F9-G4 will be administered at that visit. 


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o Premedications should be considered before any future infusions. 
o The amount of Hu5F9-G4 infused must be recorded on the case report 
form (eCRF). 
o Patients who experience a Grade 2 infusion-related reaction during the 
post-infusion observation period that does not resolve during that time 
should be observed until the AE resolves, with vital sign measurements as 
medically indicated for the management of the AE. 
• For Grade 3 or Grade 4 infusion-related reactions, where Grade 3 is 
described as prolonged infusion-related reactions (e.g., not rapidly responsive 
to symptomatic medication and/or brief interruption of infusion), or recurrence 
of symptoms following initial improvement, or where hospitalization is 
indicated for other clinical sequelae (e.g., renal impairment, pulmonary 
infiltrates). 
Grade 4 is described as having life-threatening consequences and where 
urgent intervention indicated. 
o Immediately discontinue infusion of Hu5F9-G4. 
o Begin an IV infusion of normal saline, and consider treating the patient as 
follows: 
Administer bronchodilators, epinephrine 0.2 to 1 mg of a 1:1,000 solution 
for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration and/or diphenhydramine 50 mg IV 
with methylprednisolone 100 mg IV (or equivalent), as needed. 
o The patient should be monitored until the Investigator is comfortable that 
the symptoms will not recur. 
o Patients who have Grade 4 infusion-related reactions occurring with the 
first dose (priming dose) will be permanently discontinued from study 
treatment. 
o Patients who experience Grade 3 infusion-related reactions must be given 
premedication prior to all subsequent doses.  In this setting, premedication 
with oral acetaminophen (650 mg), oral or IV diphenhydramine (25–
50 mg), and IV dexamethasone (4–20 mg), or a comparable regimen, is 


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recommended for the subsequent 2 doses.  Continued premedication with 
corticosteroids beyond these 2 doses may be administered at the 
discretion of the treating physician. 
o Patients who receive premedication with a corticosteroid and still 
experience a Grade 3 or 4 infusion-related reaction will be permanently 
discontinued from study treatment. 
o Investigators should follow their institutional guidelines for the treatment of 
anaphylaxis. 
o All patients with Grade 3 or greater infusion-related reactions will be 
observed until the AE(s) resolves or stabilizes, with vital sign 
measurements and additional evaluations, as medically indicated for the 
management of the AE(s). 
6.5.1.2. 
Tumor Lysis Syndrome 
In the case of evidence for tumor lysis syndrome associated with Hu5F9-G4, 
patients will be admitted to the hospital as clinically indicated.  Standard 
management will include vigorous IV hydration; correction of acidosis, if present; 
hypouricemic agents; and close monitoring of serum uric acid, phosphorus, and 
electrolytes.  Study treatment should be held until the patient’s condition resolves or 
stabilizes. 
6.5.1.3. 
Hemagglutination and Microangiopathy 
In the Phase 1 trial experience with Hu5F9-G4 in solid tumors and AML, 
agglutination of RBCs has been observed on peripheral smear.  Hu5F9-G4-related 
microangiopathy is a possible sequela of hemagglutination; however, it has not been 
observed in the ongoing Phase 1 clinical trials to date.  In addition, AEs may be 
associated with findings of hemagglutination.  Monitoring of hemagglutination and 
microangiopathy includes physical exam assessments, complete blood counts 
(CBCs), peripheral smears, serum chemistries, and D-dimer testing as outlined in 
the schedule of assessments (SOA).  Peripheral smears will be read by local sites 
with reporting of RBC agglutination, spherocytosis, and evidence of RBC destruction 


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(e.g., schistocytosis, fragments) when present.  The presence or absence of 
hemagglutination and/or microangiopathy on peripheral smear will be incorporated 
into the AE severity grading for hemagglutination and microangiopathy, as described 
below.  The degree of peripheral smear findings will be quantified according to the 
appropriate scale (Appendix E) for sites that have the capability to do so, but is not 
required.  
 
  AEs relating to hemagglutination and microangiopathy will be 
graded for toxicity according to the scale below. 
AE Severity Grading for Hemagglutination and Microangiopathy 
Grade 1: 
Evidence of hemagglutination and/or microangiopathy on peripheral 
blood smear AND associated clinical sequelae that is asymptomatic or 
mild, not requiring intervention  
Grade 2: 
Evidence of hemagglutination and/or microangiopathy on peripheral 
blood smear AND associated clinical sequelae that requires medical 
intervention 
Grade 3: 
Evidence of hemagglutination and/or microangiopathy on peripheral 
blood smear AND associated clinical sequelae that is medically 
significant, requiring hospitalization or prolongation of existing 
hospitalization, disabling, or limiting self-care ADLs  
Grade 4: 
Evidence of hemagglutination and/or microangiopathy on peripheral 
blood smear AND associated clinical sequelae that is life threatening or 
requires urgent intervention 
Grade 5: 
Evidence of hemagglutination and/or microangiopathy on peripheral 
blood smear AND associated clinical sequelae that results in death 
6.5.1.4. 
Anemia, Blood Cross-Matching, and Packed Red Blood Cell 
Transfusion Procedures 
Hu5F9-G4 binds to red cells and leads to erythrophagocytosis.  This, coupled with 
anemia from other causes in patients with cancers, means that care has to be taken 
with RBC cross-matching and packed red blood cell (PRBC) transfusions.  There is 
CCI


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a possibility that treatment with Hu5F9-G4 may obscure assessment of RBC 
phenotyping. 
During the Screening Period prior to initiation of Hu5F9-G4 therapy, blood cell ABO 
phenotyping for minor antigens, type and screen (ABO/Rh), and Direct Antiglobulin 
Test (DAT) will be performed for each patient as described in Section 7.3.6.7.  
This, together with using the prior phenotype, will facilitate allocation of properly 
cross-matched blood, should a blood transfusion be warranted. 
Procedure for patients after exposure to Hu5F9-G4: 
1. ABO, Rh, and DAT may be pan-reactive due to Hu5F9-G4 binding to red 
cells.  Therefore, if a non-urgent transfusion is ordered by the Investigator, 
perform the following procedures:  
• Front Type:  EDTA/glycine-acid (EGA) Treat cells ×2 (maximum) and 
Warm Wash ×4 (minimum) with 0.9% Saline. 
• Back Type:  Perform reverse anti-human globulin for both A and B. 
• If a valid ABO type cannot be obtained, mark the final report as invalid 
and notify the transfusion service for the site. 
2. Antibody screen 
If a pan-agglutinin/warm autoantibody is present in low ionic strength solution 
(LISS), repeat the antibody screen with polyethylene glycol (PeG).  Perform 
PeG adsorption studies and elution studies. 
6.5.1.4.1. 
Blood Components for Transfusion 
For all elective red cell transfusions, leukocyte-reduced units matched for the 
phenotype of the patients (as described above) will be used.  Where exact matching 
for all the specified blood groups proves impractical (e.g., for MNS), local sites will 
decide on the best matched donor units to be used.  Cytomegalovirus (CMV) 
matching (i.e., CMV seronegative units for CMV-seronegative patients) will not be 
required for this study because it will limit the inventory for antigen matching. 


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If the cross-match is incompatible, the RBC units that are Coomb's 
crossmatch-incompatible will be selected (e.g., phenotype-matched or least 
incompatible) for issue at the discretion of the local site’s Transfusion Service 
Medical Director or equivalent person, where available.  Such instances will be 
documented, along with consent signatures obtained from ordering physicians, 
according to best practices in blood bank policies and procedures. 
For emergency transfusions, the transfusion laboratory may consider using 
emergency Group O Rhesus negative units if phenotyped units are not available. 
Blood plasma therapy will be blood-type specific.  Platelets will be blood type 
compatible whenever possible, and if not, will have been tested and found not to 
have high titer anti-A or anti-B. 
6.5.2. 
Avelumab-related Events 
Detailed safety management guidelines are provided in the Avelumab PI, 
(Appendix B) for the safety issues listed below: 
• Immune-mediated reactions 
o Pneumonitis 
o Immune-mediated hepatitis 
o Immune-mediated colitis 
o Immune-mediated endocrinopathies 
• Adrenal insufficiency 
• Thyroid disorders (Hypothyroidism/Hyperthyroidism) 
• Type 1 diabetes mellitus 
o Immune-mediated nephritis and renal dysfunction  
• Other immune-related adverse reactions 
• Infusion-related reactions 
• Embryo-fetal toxicity 
To mitigate infusion-related reactions, patients have to be premedicated with an 
antihistamine and with paracetamol (acetaminophen) prior to the first 4 infusions of 


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avelumab (Section 6.1.2).  Premedication should be administered for subsequent 
avelumab doses based on clinical judgment and presence/severity of prior 
infusion-related reactions. 
Management of infusion-related reactions should follow guidelines provided in 
Table 6-2. 
Table 6-2. 
Treatment Modification for Symptoms of Infusion-related 
Reactions Associated with Avelumab 
NCI CTCAE Grade  
Treatment Modification for Avelumab 
Grade 1:  mild 
• Mild transient reaction; infusion 
interruption not indicated; intervention 
not indicated. 
• Decrease the avelumab infusion rate 
by 50% and monitor closely for any 
worsening. 
Grade 2:  moderate 
• Therapy or infusion interruption 
indicated but responds promptly to 
symptomatic treatment (for example, 
antihistamines, NSAIDs, narcotics, IV 
fluids); prophylactic medications 
indicated for ≤ 24 hours. 
• Temporarily discontinue avelumab 
infusion. 
• Resume infusion at 50% of previous 
rate once infusion-related reaction has 
resolved or decreased to at least 
Grade 1 in severity, and monitor 
closely for any worsening. 
Grade 3 or Grade 4: severe or life-threatening 
• Grade 3: Prolonged (for example, not 
rapidly responsive to symptomatic 
medication and/or brief interruption of 
infusion); recurrence of symptoms 
following initial improvement; 
hospitalization indicated for clinical 
sequelae. 
• Grade 4: Life-threatening 
consequences; urgent intervention 
indicated. 
• Stop the avelumab infusion 
immediately and disconnect infusion 
tubing from the subject. 
• Subjects have to be withdrawn 
immediately from avelumab treatment 
and must not receive any further 
avelumab treatment. 
Source:  Merck KGaA. 
Abbreviations:  IV = intravenous; NCI CTCAE = National Cancer Institute-Common Terminology Criteria for 
Adverse Event; NSAIDs = nonsteroidal anti-inflammatory drugs. 
 
Once the avelumab infusion rate has been decreased by 50% or interrupted due to 
an infusion-related reaction, it must remain decreased for the next scheduled 
infusion.  If no infusion-related reaction is observed in the next scheduled infusion 
the infusion rate may be returned to baseline at the all subsequent infusions.  If an 


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infusion-related reaction occurs, all details about drug preparation and infusion must 
be recorded on the appropriate eCRF. 
Patients should be instructed to report any delayed reactions to the Investigator 
immediately. 
Investigators should also monitor patients closely for potential infusion-related AEs 
(irAEs), which may become manifest at any time during treatment.  Such events 
include but are not limited to pneumonitis, hepatitis, colitis, endocrinopathies 
(hypothyroidism, hyperthyroidism, adrenal insufficiency, type 1 diabetes mellitus), 
myocarditis, myositis, rash. 
6.5.2.1. 
Immune-related Adverse Events 
Since inhibition of PD-L1 stimulates the immune system, irAEs may occur. 
Treatment of irAEs is mainly dependent upon severity (NCI CTCAE grade): 
• Grade 1 to 2:  treat symptomatically or with moderate dose steroids, more 
frequent monitoring 
• Grade 1 to 2 (persistent):  manage similar to high grade AE (Grade 3 to 4) 
• Grade 3 to 4:  treat with high dose corticosteroids 
Treatment of irAEs should follow guidelines presented in Table 6-3. 
Table 6-3. 
Management of Immune-Related Adverse Events 
(Avelumab) 
Gastrointestinal irAEs 
Severity of 
Diarrhea/Colitis 
(NCI CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 
Diarrhea: <4 stools/day 
over Baseline 
Colitis: asymptomatic  
Continue avelumab therapy 
Symptomatic treatment (e.g., 
loperamide) 
Close monitoring for worsening 
symptoms 
Educate patient subject to report 
worsening immediately 
If worsens: 
Treat as Grade 2, 3 or 4.  
Grade 2  
Diarrhea: 4 to 6 stools 
per day over Baseline; 
Withhold avelumab therapy 
Symptomatic treatment 
If improves to Grade ≤1:  
Resume avelumab therapy 


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IV fluids indicated 
<24 hours; not 
interfering with ADL 
Colitis: abdominal pain; 
blood in stool  
 
If persists >5-7 days or recurs: 
Treat as Grade 3 or 4. 
Grade 3 to 4 
Diarrhea (Grade 3): 
≥7 stools per day over 
Baseline; incontinence; 
IV fluids ≥24 h; 
interfering with ADL 
Colitis (Grade 3):  
severe abdominal pain, 
medical intervention 
indicated, peritoneal 
signs 
Grade 4: life- 
Withhold avelumab for Grade 3. 
Permanently discontinue 
avelumab for Grade 4 or 
recurrent Grade 3. 
 
1.0 to 2.0 mg/kg/day prednisone 
IV or equivalent 
Add prophylactic antibiotics for 
opportunistic infections  
Consider lower endoscopy 
If improves:  
Continue steroids until Grade ≤1, then 
taper over at least 1 month; resume 
avelumab therapy following steroids 
taper (for initial Grade 3).  
 
If worsens, persists >3 to 5 days, or 
recurs after improvement: 
Add infliximab 5 mg/kg (if no 
contraindication). Note: infliximab 
should not be used in cases of 
perforation or sepsis. 
Dermatological irAEs 
Grade of Rash 
(NCI CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 to 2  
Covering ≤30% body 
surface area 
Continue avelumab therapy  
Symptomatic therapy (for 
example, antihistamines, topical 
steroids) 
If Grade 2 persists >1 to 2 weeks or 
recurs:  
Withhold avelumab therapy  
Consider skin biopsy  
 
Consider 0.5-1.0 mg/kg/day prednisone 
or equivalent. Once improving, taper 
steroids over at least 1 month, consider 
prophylactic antibiotics for opportunistic 
infections, and resume avelumab 
therapy following steroids taper. 
If worsens:  
Treat as Grade 3 to 4. 
Grade 3 to 4 
Grade 3: Covering 
>30% body surface 
area;  
Grade 4: Life-
threatening 
consequences  
Withhold avelumab for Grade 3. 
Permanently discontinue for 
Grade 4 or recurrent Grade 3.  
Consider skin biopsy  
Dermatology consult  
1.0 to 2.0 mg/kg/day prednisone 
or equivalent 
Add prophylactic antibiotics for 
opportunistic infections  
If improves to Grade ≤1:  
Taper steroids over at least 1 month; 
resume avelumab therapy following 
steroids taper (for initial Grade 3). 
Pulmonary irAEs 
Grade of Pneumonitis 
(NCI CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 
Consider withholding avelumab 
Re-assess at least every 3 weeks 


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Radiographic changes 
only  
therapy  
Monitor for symptoms every 2 to 
3 days  
Consider Pulmonary and 
Infectious Disease consults  
If worsens:  
Treat as Grade 2 or Grade 3 to 4.  
Grade 2 
Mild to moderate new 
symptoms  
Withhold avelumab therapy 
Pulmonary and Infectious 
Disease consults 
Monitor symptoms daily; consider 
hospitalization  
1.0 to 2.0 mg/kg/day prednisone 
or equivalent 
Add prophylactic antibiotics for 
opportunistic infections  
Consider bronchoscopy, lung 
biopsy  
Re-assess every 1 to 3 days  
If improves:  
When symptoms return to Grade ≤1, 
taper steroids over at least 1 month, 
and then resume avelumab therapy 
following steroids taper  
If not improving after 2 weeks or 
worsening or for recurring Grade 2:  
Treat as Grade 3 to 4.  
Grade 3 to 4 
Grade 3: Severe new 
symptoms; 
New/worsening 
hypoxia; 
Grade 4:  Life-
threatening  
Permanently discontinue 
avelumab therapy. 
Hospitalize. 
Pulmonary and Infectious 
Disease consults. 
1.0 to 2.0 mg/kg/day prednisone 
or equivalent 
Add prophylactic antibiotics for 
opportunistic infections  
Consider bronchoscopy, lung 
biopsy  
If improves to Grade ≤1:  
Taper steroids over at least 1 month  
If not improving after 48 hours or 
worsening:  
Add additional immunosuppression (for 
example, infliximab, cyclophosphamide, 
IV immunoglobulin, or mycophenolate 
mofetil)  
Hepatic irAEs 
Grade of Liver Test 
Elevation 
(NCI CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 
Grade 1 AST or ALT 
>ULN to 3.0 x ULN 
and/or Total bilirubin 
>ULN to 1.5 x ULN  
Continue avelumab therapy 
Continue liver function monitoring  
If worsens:  
Treat as Grade 2 or 3 to 4. 
Grade 2 
AST or ALT >3.0 to 
≤5 x ULN and/or total 
bilirubin >1.5 to ≤3 x 
ULN  
Withhold avelumab therapy 
Increase frequency of monitoring 
to every 3 days 
If returns to Grade ≤1: 
Resume routine monitoring; resume 
avelumab therapy. 
If elevation persists >5 to 7 days or 
worsens:  
Treat as Grade 3 to 4. 
Grade 3 to 4 
AST or ALT >5 x ULN 
and/or total bilirubin 
>3 x ULN  
Permanently discontinue 
avelumab therapy  
Increase frequency of monitoring 
to every 1 to 2 days  
1.0 to 2.0 mg/kg/day prednisone 
or equivalent 
If returns to Grade ≤1:  
Taper steroids over at least 1 month  
If does not improve in >3 to 5 days, 
worsens or rebounds:  
Add mycophenolate mofetil 1 gram (g) 
twice daily  


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Add prophylactic antibiotics for 
opportunistic infections  
Consult gastroenterologist/ 
hepatologist 
Consider obtaining MRI/CT scan 
of liver and liver biopsy if clinically 
warranted  
If no response within an additional 3 to 
5 days, consider other 
immunosuppressants according to local 
guidelines. 
Renal irAEs 
Grade of Creatinine 
Increased 
(NCI CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 
Creatinine increased 
>ULN to 1.5 x ULN 
Continue avelumab therapy 
Continue renal function monitoring 
If worsens: 
Treat as Grade 2 to 3 or 4. 
Grade 2 to 3 
Creatinine increased 
>1.5 and ≤6 x ULN 
Withhold avelumab therapy 
Increase frequency of monitoring 
to every 3 days 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent. 
Add prophylactic antibiotics for 
opportunistic infections 
Consider renal biopsy 
If returns to Grade ≤1: 
Taper steroids over at least 1 month, and 
resume avelumab therapy following 
steroids taper. 
If worsens: 
Treat as Grade 4. 
Grade 4 
Creatinine increased 
>6 x ULN 
Permanently discontinue 
avelumab therapy 
Monitor creatinine daily 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent. 
Add prophylactic antibiotics for 
opportunistic infections 
Consider renal biopsy 
Nephrology consult 
If returns to Grade ≤1: 
Taper steroids over at least 1 month. 
Cardiac irAEs 
Myocarditis 
Initial Management 
Follow-up Management 
New onset of cardiac 
signs or symptoms 
and / or new 
laboratory cardiac 
biomarker elevations 
(e.g., troponin, CK-MB, 
BNP) or cardiac 
imaging abnormalities 
suggestive of 
myocarditis.  
Withhold avelumab therapy. 
Hospitalize. 
In the presence of life-threatening 
cardiac decompensation, 
consider transfer to a facility 
experienced in advanced heart 
failure and arrhythmia 
management. 
Cardiology consult to establish 
etiology and rule-out immune-
mediated myocarditis.  
Guideline based supportive 
treatment as per cardiology 
consult.* 
If symptoms improve and 
immune-mediated etiology is ruled out, 
re-start avelumab therapy. 
 
If symptoms do not improve/worsen, 
viral myocarditis is excluded, and 
immune-mediated etiology is suspected 
or confirmed following cardiology 
consult, manage as immune-mediated 
myocarditis. 


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Consider myocardial biopsy if 
recommended per cardiology 
consult. 
Immune-mediated 
myocarditis 
Permanently discontinue 
avelumab. 
Guideline based supportive 
treatment as appropriate as per 
cardiology consult.* 
1.0 to 2.0 mg/kg/day prednisone 
or equivalent 
Add prophylactic antibiotics for 
opportunistic infections. 
Once improving, taper steroids over at 
least 1 month. 
 
If no improvement or worsening, 
consider additional 
immunosuppressants (e.g., 
azathioprine, cyclosporine A). 
*Local guidelines, or e.g., European Society of Cardiology (ESC) or American Heart Association 
(AHA) Guidelines 
ESC Guidelines website: 
https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines 
AHA Guidelines website: 
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001 
Endocrine irAEs 
Endocrine Disorder 
Initial Management 
Follow-up Management 
Grade 1 or Grade 2 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, 
adrenal insufficiency, 
type I diabetes 
mellitus) 
Continue avelumab therapy 
Endocrinology consult if needed 
 
Start thyroid hormone 
replacement therapy (for 
hypothyroidism), anti-thyroid 
treatment (for hyperthyroidism), 
corticosteroids (for adrenal 
insufficiency) or insulin (for Type 
I diabetes mellitus) as 
appropriate.   
 
Rule-out secondary 
endocrinopathies (i.e., 
hypopituitarism / hypophysitis) 
Continue hormone 
replacement/suppression and 
monitoring of endocrine function as 
appropriate. 
Grade 3 or Grade 4 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, 
adrenal insufficiency, 
type I diabetes 
mellitus) 
Withhold avelumab therapy 
Consider hospitalization 
Endocrinology consult 
 
Start thyroid hormone 
replacement therapy (for 
hypothyroidism), anti-thyroid 
treatment (for hyperthyroidism), 
corticosteroids (for adrenal 
insufficiency) or insulin (for type I 
diabetes mellitus) as appropriate.  
 
Rule-out secondary 
endocrinopathies (i.e., 
hypopituitarism / hypophysitis) 
Resume avelumab once symptoms 
and/or laboratory tests improve to 
Grade ≤1 (with or without hormone 
replacement/suppression). 
 
Continue hormone 
replacement/suppression and 
monitoring of endocrine function as 
appropriate.  


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Hypopituitarism/ 
Hypophysitis 
(secondary 
endocrinopathies) 
If secondary thyroid and/or 
adrenal insufficiency is confirmed 
(i.e., subnormal serum FT4 with 
inappropriately low TSH and/or 
low serum cortisol with 
inappropriately low ACTH): 
• Refer to endocrinologist for 
dynamic testing as indicated 
and measurement of other 
hormones (FSH, LH, 
GH/IGF-1, PRL, testosterone 
in men, estrogens in women)  
• Hormone 
replacement/suppressive 
therapy as appropriate  
• Perform pituitary MRI and 
visual field examination as 
indicated 
If hypophysitis confirmed: 
• Continue avelumab if mild 
symptoms with normal MRI.  
Repeat the MRI in 1 month 
• Withhold avelumab if 
moderate, severe or 
life-threatening symptoms of 
hypophysitis and/or abnormal 
MRI.  Consider hospitalization. 
Initiate corticosteroids (1 to 
2 mg/kg/day prednisone or 
equivalent) followed by 
corticosteroids taper during at 
least 1 month. 
• Add prophylactic antibiotics for 
opportunistic infections. 
Resume avelumab once symptoms and 
hormone tests improve to Grade ≤1 
(with or without hormone replacement). 
 
In addition, for hypophysitis with 
abnormal MRI, resume avelumab only 
once shrinkage of the pituitary gland on 
MRI/CT scan is documented.  
 
Continue hormone 
replacement/suppression therapy as 
appropriate. 
Other irAEs (not described above) 
Grade of other irAEs 
(NCI CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 2 or Grade 3 
clinical signs or 
symptoms suggestive 
of a potential irAE 
Withhold avelumab therapy 
pending clinical investigation 
If irAE is ruled out, manage as 
appropriate according to the diagnosis 
and consider re-starting avelumab 
therapy 
If irAE is confirmed, treat as Grade 2 or 
3 irAE. 
Grade 2 irAE or first 
occurrence of Grade 
3 irAE 
Withhold avelumab therapy 
1.0 to 2.0 mg/kg/day prednisone 
or equivalent 
Add prophylactic antibiotics for 
opportunistic infections  
Specialty consult as appropriate 
If improves to Grade ≤1:  
Taper steroids over at least 1 month 
and resume avelumab therapy 
following steroids taper. 
Recurrence of same 
Grade 3 irAEs 
Permanently discontinue 
avelumab therapy 
1.0 to 2.0 mg/kg/day 
If improves to Grade ≤1:  
Taper steroids over at least 1 month. 


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prednisone or equivalent 
Add prophylactic antibiotics for 
opportunistic infections  
Specialty consult as appropriate 
Grade 4  
Permanently discontinue 
avelumab therapy 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent and/or 
other immunosuppressant as 
needed 
Add prophylactic antibiotics for 
opportunistic infections  
Specialty consult. 
If improves to Grade ≤1:  
Taper steroids over at least 1 month 
Requirement for 
10 mg per day or 
greater prednisone or 
equivalent for more 
than 12 weeks for 
reasons other than 
hormonal replacement 
for adrenal 
insufficiency 
 
Persistent Grade 2 or 
3 irAE lasting 12 weeks 
or longer 
Permanently discontinue 
avelumab therapy 
Specialty consult 
 
Source:  Merck KGaA. 
Abbreviations:  ACTH = adrenocorticotropic hormone; ADL = activities of daily living; ALT = alanine 
aminotransferase; AST = aspartate aminotransferase; BNP = B-type natriuretic peptide; CK-MB = creatine 
kinase MB;  CT =  computed tomography; FSH = follicle-stimulating hormone; GH = growth hormone; 
IGF-1 = insulin-like growth factor 1; irAE = immune related adverse event; IV = intravenous; LH = luteinizing 
hormone; MRI = magnetic resonance imaging; NCI CTCAE = National Cancer Institute Common Terminology 
Criteria for Adverse Events; PRL = prolactin;T4 = thyroxine; TSH = thyroid stimulating hormone; ULN = upper 
limit of normal. 
 
6.6. 
Prohibited Medications 
6.6.1. 
Hu5F9-G4 
Anti-cancer therapies (including chemotherapy, hormonal therapy, and 
investigational agents) are prohibited while patients are on study therapy.  
However, low dose steroids (oral prednisone or equivalent ≤10 mg per day or 
equivalent), localized non-CNS radiotherapy, previous hormonal therapy with LHRH 
agonists for prostate cancer, treatment with bisphosphonates or RANKL inhibitors 
and other supportive care medicines are allowed during the study. 


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6.6.2. 
Avelumab 
The following treatments must not be administered during the trial except where 
unavoidable for the treatment of adverse events: 
• Immunotherapy, immunosuppressive drugs (that is, chemotherapy or 
systemic corticosteroids) except: 
o When required for the treatment of immune-related adverse events or 
infusion-related reactions/hypersensitivity  
o Systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone 
or equivalent 
o Systemic corticosteroids for management of patients with allergy to CT IV 
Radiographic Contrast Media. 
• Administration of a live vaccine within 28 days prior to study treatment. 
• Growth factors (granulocyte colony stimulating factor or granulocyte 
macrophage colony stimulating factor).  Exception:  Erythropoietin and 
darbepoietin alpha may be prescribed at the investigator’s discretion. 
• Herbal remedies with immunostimulating properties (for example, mistletoe 
extract) or known to potentially interfere with major organ function (for 
example, hypericin). 
The following non-drug therapies must not be administered during the trial: 
• Surgery to any tumor lesion for symptom management or tumor control is not 
permitted during the study treatment.  For any other surgical interventions 
planned during the study, study treatment should be delayed to allow patient’s 
recovery, for up to a maximum of 4 weeks. 
• Radiotherapy with the exception of palliative bone-directed radiotherapy. 
Palliative short-course, limited-field (i.e., ≤10 fractions and ≤30% bone marrow 
involvement or per institutional standard) bone-directed radiotherapy may be 
administered during the trial. 


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6.7. 
Post-therapy Follow-up and Patient Study Completion 
Patients who complete, terminate, or decline further treatment should return for their 
Safety Follow-up Visit 30 days (± 1 week) after their last dose of last study drug 
received.  The Safety Follow-up Visit assessments are described in Section 7.3.16.  
Patients will receive Safety Follow-up Contact by phone 90 days after their last dose 
of last study drug received (± 5 days).  Patients who develop study drug-related AEs 
or SAEs within the 90-day period will be seen by the study physician. 
Patients are considered to have completed study drug treatment when they finish 
the Safety Follow-up Visit 30 days (± 1 week) after their last dose of last study drug 
received, unless they are experiencing ongoing study drug-related AEs and serious 
adverse events (SAEs).  For patients being followed for ongoing SAEs or study 
drug-related AEs, follow-up visits will continue at least every 4 weeks until resolution 
or return to baseline, stabilization of the event, the patient is lost to follow-up or 
withdraws consent, or the Medical Monitor deems it necessary, whichever occurs 
first.  If a patient begins another anti-cancer therapy, Safety Follow-up Visits will 
stop. 
All patients, including those who discontinue study drug early, will be followed for 
response until progressive disease (PD) or new anti-cancer therapy and, if feasible, 
for survival (patients will be contacted every 3 months [± 1 month] from the date of 
the Safety Follow-up Visit, 5 years from the date that the last patient is enrolled into 
the study, or full withdrawal of consent) until death or study closure, whichever 
occurs first.  For any patient who dies during this period, the cause of death must be 
reported to the Sponsor.  Patients are considered to have completed study 
participation when they are no longer followed for disease progression or survival, or 
they withdraw consent. 


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7. STUDY EVALUATIONS 
7.1. 
Schedules of Assessment for Part 1 and Part 2 
Table 7-1 outlines the assessments for Study Parts 1 and 2, Dose Level 1 and 
Table 7-2 outlines the assessments for Study Parts 1 and 2, Dose Level 2.  Unless 
otherwise noted procedures are to be completed prior to any study drug infusion.  
Table 7-3 outlines the assessments for follow-up (for Part 1 and Part 2) of the study.  
Table 7-4 outlines the blood sampling times for PK, 
 and RO. 
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Table 7-1. 
Schedule of Assessments (Study Part 1 and Part 2, Dose Level 1) 
Cycle 
SC 
Priming Cycle 1 (35 days) 
Cycle 2 (28 days) 
Cycle 3 (28 days) 
Cycles 4+ (28 days) 
Cycle Day 
SC 
1 
2 
8 
9 
15 22 
29 
1 
15 
1 
15 
1 
15 
Visit Window 
-30 
None 
±1 Day 
± 2 Days 
± 2 Days  
± 2 Days 
Assessments 
 
 
Informed Consent 
X 
 
 
Demographics 
X 
 
 
Medical and cancer history 
X 
 
 
Eligibility criteria 
X 
 
 
Cohort assignmenta 
X 
 
 
Physical examinationb,f 
X 
X 
X 
X 
X 
X 
Xb 
Xb 
Xb 
 
Vital signsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight 
X 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
 
ECGd 
X 
X 
X 
X 
 
 
ECOG performance statusf 
X 
X 
X 
X 
X 
 
Pregnancy teste,f 
X 
X 
X 
X 
X 
 
Serum chemistryf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC, differential, platelets, 
reticulocytesf 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Peripheral blood smearf,g 
X 
X 
X 
X 
X 
X 
X 
 
 
Serum uric acid, phosphorousf 
X 
X 
X 
X 
X 
X 
X 
 
 
Haptoglobin, D-dimer, thrombin 
time, plasma fibrinogenf 
X 
 
X 
X 
 
X 
X 
X 
X 
 
X 
 
X 
 
PT/INR, aPTTf 
X 
X 
X 
X 
X 
 
ACTH, FSH, TSHf 
X 
 
 
X 
 
 
 
 
 
X 
 
 
X s 
 
T3 (Total), T4 (Free)f 
X 
 
 
X 
 
 
 
 
 
X 
 
 
Xs 
 
ABO/Rh, DATf,h 
X 
 
 
Urinalysisf 
X 
X 
X 
 
 


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Cycle 
SC 
Priming Cycle 1 (35 days) 
Cycle 2 (28 days) 
Cycle 3 (28 days) 
Cycles 4+ (28 days) 
Cycle Day 
SC 
1 
2 
8 
9 
15 22 
29 
1 
15 
1 
15 
1 
15 
Visit Window 
-30 
None 
±1 Day 
± 2 Days 
± 2 Days  
± 2 Days 
Assessments 
 
 
Pharmacokineticsi 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
Q3 cycles 
See 
Table 7-
4 
 
Antidrug antibodiesf,l 
X 
X 
X 
Q3 cycles  
 
Tumor biopsym 
X 
X 
 
 
Tumor markers, if applicablen 
Xn 
X 
X 
X n 
 
Response assessmento 
Xp 
 
 
 
 
 
 
 
 
 
Xq 
 
Q2C 
odd 
cycleq 
 
DLT assessmentr 
X 
 
 
Adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hu5F9-G4 premedicationt 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Hu5F9-G4 administration 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Avelumab premedicationt 
 
 
 
X 
 
 
X 
 
X 
X 
 
 
 
 
Avelumab administration 
X 
X 
X 
X 
X 
X 
X 
X 
 
Abbreviations:  1st = first; ABO = any of the four blood groups A, B, AB, and O comprising the ABO system; ADAs = anti-drug antibodies; 
aPTT = activated partial thromboplastin time; CBC = complete blood count; DAT = direct antiglobulin test; DLT = dose-limiting toxicity; 
ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance status; EOT = End of Treatment; 
INR = international normalized ratio; PE = physical examination; PT = prothrombin time; Rh = Rhesus factor; RO = receptor occupancy; 
SC = screening; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid stimulating hormone. 
 
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Hu5F9-G4 
Protocol 5F9006, Amendment 3 
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Footnotes: 
a. First dose of Hu5F9-G4 (priming dose) must be given within 30 days of consent. 
b. Full PE is required at Screening, a symptom-directed PE is acceptable thereafter; height should be recorded during Screening only; weight 
should be recorded during Screening and on Day 1 of each cycle. 
c. Prior to infusion and within 30 minutes after each infusion (if applicable); vital signs should include heart rate, respiratory rate, blood 
pressure, and temperature. Height should be recorded during Screening only. 
d. A single ECG will be performed at Screening. Triplicate ECGs will be performed at the visits indicated after Screening, within 2 hours prior 
to avelumab infusion if applicable, and within 30 minutes of the end of Hu5F9-G4 infusion; additional guidance is provided in Section 7.3.2. 
e. A urine or serum pregnancy test is required (only for women of childbearing potential; excluding patients who are post-menopausal with 
absence of menses for at least 1 year and/or surgically sterilized) at Screening and within 72 hours prior to dosing on Day 1. The Day 1 
pregnancy test does not need to be repeated if the Screening pregnancy test was performed within the 72 hours prior to dosing. After 
Screening, all pregnancy tests can be urine or serum pregnancy tests and should be performed on Day 1 of every cycle; additional 
guidance is provided in Section 7.3.5. Contraceptive requirements for female patients are outlined in Section 4.6.1, and for male patients 
in Section 4.6.2. 
f. Pre-infusion assessments may be performed up to 72 hours before study drug treatment. Most laboratory assessments will be performed 
locally at each study center's laboratory by means of their established methods; analytes to be assessed by the local laboratory or 
specialty laboratories are presented in Table 7-5. 
g. Peripheral blood smear slides from Cycle 1 will be retained and sent to the Sponsor for storage. Collection guidelines are provided in 
Section 7.3.6.3. Peripheral blood smears are also to be collected 1 hour (± 30 minutes) after completion of any blood transfusion. 
h. Type and screen; additional guidance is provided in Section 7.3.6.7 and Table 7-5. 
i. Refer to Table 7-4 for PK time point details; samples should be drawn on the contralateral arm from where the study drugs are being 
infused and they should not be drawn from central lines where the relevant study drugs have been previously infused; additional guidance 
is provided in Section 7.3.8. 
k. Not applicable. 
I. ADAs to Hu5F9-G4- - should be assessed on Day 1 of Cycles 1, 2, 3, and 4 and then every 3 cycles until Cycle 13, at the End 
of Treatment Visit, a~
ay Safety Follow-up Visit. Additional guidance is provided in Section 7 .3.10. 
m. Biopsies are to be collected during the Screening Period prior to first dose and on Cycle 3 Day 1 (± 2 weeks); tumor biopsies are 
mandatory for Part 2 where medically feasible. 
n. Tumor markers should be obtained at Screening. If applicable, they should also be obtained on Day 1 of Cycles 2, 3, and 4. From Cycle 5 
and onward, they may be obtained every 2 cycles; additional guidance is provided in Section 7.3.12. 
o. After Cycle 3, the adjustment window is ± 2 weeks to coordinate with treatment cycles; additional guidance is provided in Section 7 .3.12. 
p. Historic imaging may be used for Screening diagnostic imaging if performed within 30 days of the first dose of Hu5F9-G4; additional 
guidance is provided in Section 7.3.12. 
Forty Seven Inc. 
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Hu5F9-G4 
Protocol 5F9006, Amendment 3 
Page 106 of 160 
 
Forty Seven Inc. 
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Footnotes:  
q. Efficacy assessment should be conducted at ± 1 week of the Cycle 3 Day 1 visit, and then at ± 2 weeks of the Day 1 visit of every other 
subsequent cycle (i.e., Day 1 of Cycles 5, 7, 9, and so on); additional guidance is provided in Section 7.3.12.  Patients who discontinue 
from treatment prior to documented confirmed PD will be followed for disease progression according to the schedule of assessment until 
documented confirmed PD. 
r. DLT assessment will be done for the Safety Run-in Cohort only and will be assessed through the first 5 weeks of the study; additional 
guidance is provided in Section 3.2.1. 
s. Starting with Cycle 4, TSH and T4 assessments to be performed every 8 weeks (i.e., Day 1 of Cycles 4, 6, 8, and so on). 
t. Premedication details are provided in Section 6.1.2. 
 


Hu5F9-G4 
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Table 7-2. 
Schedule of Assessments (Study Part 1 and Part 2, Dose Level 2) 
Cycle 
SC 
 
Priming Cycle 1 
(35 days) 
Cycle 2 
(28 days) 
Cycle 3 
(28 days) 
Cycles 4+  
(28 days) 
Cycle Day 
SC 
1 
2 
8 
9 
11 
15 22 
29 
1 
8 
15 
22 
1 
15 
1 
15 
Visit Window 
-30 
None 
 
±1 Day 
± 2 Days 
± 2 Days  
± 2 Days 
Assessments 
 
 
 
 
Informed Consent 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical and cancer history 
X 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
Cohort assignmenta 
X 
 
 
 
 
Physical examinationb,f 
X 
X 
X 
X 
X 
X 
X 
Xb 
 
Xb 
Xb 
 
Vital signsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
ECGd 
X 
X 
X 
 
X 
 
 
 
ECOG performance statusf 
X 
X 
 
X 
 
X 
X 
 
Pregnancy teste,f 
X 
X 
 
X 
 
X 
X 
 
Serum chemistryf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC, differential, platelets, 
reticulocytesf 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Peripheral blood smearf,g 
X 
X 
X 
 
X 
X 
X 
 
X 
 
 
Serum uric acid, phosphorousf 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Haptoglobin, D-dimer, thrombin time, 
plasma fibrinogenf 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
X 
 
X 
 
PT/INR, aPTTf 
X 
X 
 
X 
 
X 
X 
 
ACTH, FSH, TSHf 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X s 
 
T3 (Total), T4 (Free)f 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Xs 
 
ABO/Rh, DATf,h 
X 
 
 
 
 
Urinalysisf 
X 
 
X 
X 
 
 
 


Hu5F9-G4 
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Forty Seven Inc. 
Confidential 
Cycle 
SC 
 
Priming Cycle 1 
(35 days) 
Cycle 2 
(28 days) 
Cycle 3 
(28 days) 
Cycles 4+  
(28 days) 
Cycle Day 
SC 
1 
2 
8 
9 
11 
15 22 
29 
1 
8 
15 
22 
1 
15 
1 
15 
Visit Window 
-30 
None 
 
±1 Day 
± 2 Days 
± 2 Days  
± 2 Days 
Assessments 
 
 
 
 
Pharmacokineticsi 
 
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Q3 cycles 
See 
Table 7-4 
 
Antidrug antibodiesf,l 
X 
 
X 
 
X 
Q3 cycles  
 
Tumor biopsym 
X 
 
 
X 
 
 
Tumor markers, if applicablen 
Xn 
 
X 
 
X 
X n 
 
Response assessmento 
Xp 
 
 
 
 
 
 
 
 
 
 
 
 
Xq 
 
Q2C 
odd cycleq 
 
DLT assessmentr 
 
X 
 
 
 
Adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hu5F9-G4 premedicationt 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Hu5F9-G4 administration 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Avelumab premedicationt 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
Avelumab administration 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Abbreviations:  1st = first; ABO = any of the four blood groups A, B, AB, and O comprising the ABO system; ADAs = anti-drug antibodies; aPTT = 
activated partial thromboplastin time; CBC = complete blood count; DAT = direct antiglobulin test; DLT = dose-limiting toxicity; ECG = 
electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance status; EOT = End of Treatment; INR = international 
normalized ratio; PE = physical examination; PT = prothrombin time; Rh = Rhesus factor; RO = receptor occupancy; SC = screening; T3 = 
triiodothyronine; T4 = thyroxine; TSH = thyroid stimulating hormone. 
 
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Hu5F9-G4 
Protocol 5F9006, Amendment 3 
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Footnotes: 
a. First dose of Hu5F9-G4 (priming dose) must be given within 30 days of consent. 
b. Full PE is required at Screening, a symptom-directed PE is acceptable thereafter; height should be recorded during Screening only; weight 
should be recorded during Screening and on Day 1 of each cycle. 
c. Prior to infusion and within 30 minutes after each infusion (if applicable); vital signs should include heart rate, respiratory rate, blood pressure, 
and temperature. Height should be recorded during Screening only. Weight should be recorded at Screening and D1 of each Cycle only. 
d. A single ECG will be performed at Screening. Triplicate ECGs will be performed at the visits indicated after Screening, within 2 hours prior to 
avelumab infusion if applicable, and within 30 minutes of the end of Hu5F9-G4 infusion; additional guidance is provided in Section 7.3.2. 
e. A urine or serum pregnancy test is required (only for women of childbearing potential; excluding patients who are post-menopausal with 
absence of menses for at least 1 year and/or surgically sterilized) at Screening and within 72 hours prior to dosing on Day 1. The Day 1 
pregnancy test does not need to be repeated if the Screening pregnancy test was performed within the 72 hours prior to dosing. After 
Screening, all pregnancy tests can be urine or serum pregnancy tests and should be performed on Day 1 of every cycle; additional guidance is 
provided in Section 7.3.5. Contraceptive requirements for female patients are outlined in Section 4.6.1 , and for male patients in Section 4.6.2. 
f. Pre-infusion assessments may be performed up to 72 hours before study drug treatment. Most laboratory assessments will be performed 
locally at each study center's laboratory by means of their established methods; analytes to be assessed by the local laboratory or specialty 
laboratories are presented in Table 7-5. 
g. Peripheral blood smear slides from Cycle 1 will be retained and sent to the Sponsor for storage. Collection guidelines are provided in Section 
7.3.6.3. Peripheral blood smears are also to be collected 1 hour (± 30 minutes) after completion of any blood transfusion. 
h. Type and screen; additional guidance is provided in Section 7.3.6.7 and Table 7-5. 
i. Refer to Table 7-4 for PK time point details; samples should be drawn on the contralateral arm from where the study drugs are being infused 
and they should not be drawn from central lines where the relevant study drugs have been previously infused; additional guidance is provided 
in Section 7.3.8. 
k. Not applicable. 
I. ADAs to Hu5F9-G4- - should be assessed on Day 1 of Cycles 1, 2, 3, and 4 and then every 3 cycles until Cycle 13, at the End of 
Treatment Visit, an~ 
Safety Follow-up Visit. Additional guidance is provided in Section 7.3.10. 
m. Biopsies are to be collected during the Screening Period prior to first dose and on Cycle 3 Day 1 (± 2 weeks); tumor biopsies are 
mandatory for Part 2 where medically feasible. 
n. Tumor markers should be obtained at Screening. If applicable, they should also be obtained on Day 1 of Cycles 2, 3, and 4. From Cycle 5 
and onward, they may be obtained every 2 cycles; additional guidance is provided in Section 7.3.12. 
o. After Cycle 3, the adjustment window is ± 2 weeks to coordinate with treatment cycles; additional guidance is provided in Section 7 .3.12. 
p. Historic imaging may be used for Screening diagnostic imaging if performed within 30 days of the first dose of Hu5F9-G4; additional guidance 
is provided in Section 7.3.12. 
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Footnotes:  
q. Efficacy assessment should be conducted at ± 1 week of the Cycle 3 Day 1 visit, and then at ± 2 weeks of the Day 1 visit of every other 
subsequent cycle (i.e., Day 1 of Cycles 5, 7, 9, and so on); additional guidance is provided in Section 7.3.12.  Patients who discontinue from 
treatment prior to documented confirmed PD will be followed for disease progression according to the schedule of assessment until 
documented confirmed PD. 
r. DLT assessment will be done for the Safety Run-in Cohort only and will be assessed through the first 5 weeks of the study; additional 
guidance is provided in Section 3.2.1. 
s. Starting with Cycle 4, TSH and T4 assessments to be performed every 8 weeks (i.e., Day 1 of Cycles 4, 6, 8, and so on). 
t. Premedication details are provided in Section 6.1.2. 
 


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Table 7-3. 
Schedule of Assessments for Follow-up (Study Part 1 and Part 2, All Dose Levels) 
Assessments 
End of 
Treatment 
Safety 
Follow-up Visit 
Safety 
Follow-up 
Contact 
Long-term 
Follow-up 
Survival 
Follow-up 
Within 14 days 
of EOT 
decision 
30 days after last 
dose of study 
drug 
90 days after last 
dose of study 
drug 
Every 8 weeks 
until PD or new 
anti-cancer 
therapy 
Up to 
60 months 
from LPE 
Visit Window 
± 1 Week 
± 5 Days 
± 2 Weeks 
± 1 Month 
Physical examination (symptom directed) 
 
X 
 
 
 
Vital signs 
 
X 
 
 
 
Weight 
 
X 
 
 
 
ECOG performance status (Appendix D) 
 
X 
 
 
 
Serum or urine pregnancy testa  
 
X 
 
 
 
Serum chemistry  
 
X 
 
 
 
CBC with differential, platelets, reticulocytes  
X 
 
 
 
TSH, T3 (Total), T4 (Free) 
 
X 
 
 
 
Pharmacokinetics for Hu5F9-G4 and 
avelumab  
X 
X 
 
 
 
Antidrug antibodies  
X 
X 
 
 
 
Tumor markers, if applicable 
Xc 
 
Q8W 
 
Response assessmentc 
Xc 
Xc 
 
Q8W 
 
Adverse events 
X 
X 
Xd 
Q4We 
Concomitant medications 
X 
X 
 
 
Survival follow-up and new anti-cancer 
therapy 
 
 
Xd 
 
Q3 Months 
 
Abbreviations:  AE = adverse event; ECOG = Eastern Cooperative Oncology Group; EOT = End of Treatment; LPE = last patient enrolled; 
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PD = progressive disease; Q3 = every 3; Q4W = every 4 weeks; Q8W = once every 8 weeks; Q3 months = once every 3 months; SAE = serious 
adverse event; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid stimulating hormone. 
 
Footnotes:  
a. Contraceptive requirements for female patients are outlined in Section 4.6.1, and for male patients in Section 4.6.2. 
 
c. Response assessment is required only if not completed within the 4 weeks prior to the Safety Follow-up Visit.  EOT response assessment is 
required only if not completed within the 4 weeks prior to the EOT Visit.  Additional guidance is provided in Section 7.3.12. 
d. Safety follow-up contact is to be by phone.  Patients who develop study drug-related AEs or SAEs within the 90-day period will be seen by the 
study physician. 
e. Any ongoing SAEs and study drug-related AEs and new SAEs reported after the AE collection period (i.e., assessed as study drug-related 
should be followed every 4 weeks until resolution or return to baseline; stabilization of the event; the patient is lost to follow-up, withdraws 
consent, or starts another anti-cancer therapy; or when the Medical Monitor deems it necessary, whichever occurs first. 
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Table 7-4. 
Blood Sampling Times for PK 
(Study Part 1 and Part 2) 
Cycle 
Time Points 
1 
2 
3 
4+ 
EOT 
SFU 
Day 
1 
2 
8 
9 
22 
1 
15 
1 
1 
Variable 
Variable 
PK (Hu5F9-G4 and avelumab) 
Pre-study drug infusion (within 12 hours) 
X 
X 
xa 
X 
xa 
xa,b 
xe 
X 
1 hour (±15 minutes) after Hu5F9-G4 infusion 
X 
X 
24 hours (±15 minutes) after Hu5F9-G4 infusion, 
X 
X 
Part 1 only 
Abbreviations: C = cycle; EOT = End of Treatment; PD = progressive disease; PK = pharmacokinetics; SFU = Safety Follow-up. 
a. Hu5F9-G4 sample may be collected before the avelumab infusion at same time as the "pre-avelumab infusion" PK time point. 
b. Starting with Cycle 4, samples are to be collected every third cycle until Cycle 13, and then the End of Treatment Visit. 
if the visit occurs prior to Cycle 2. 
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7.2. 
Screening Assessments 
Refer to the schedule provided in Table 7-1 for specific timing of screening 
procedures. 
The patient must be willing and able to sign and date the ICF before any Screening 
assessments or study-specific tests may be performed.  All patients who are 
enrolled will be given a unique study number that will be used to identify the patient 
throughout the study. 
Screening assessments will be completed within a 30-day Screening Period prior to 
the first dose of study drug.  Screening assessments may be repeated during the 
30-day Screening period.  Screening assessments may be used for pre-infusion 
assessments on Cycle 1, Day 1 dosing if performed within 72 hours of study drug 
administration.  Assessments performed as part of standard of care prior to ICF may 
be used if they are within the required Screening period.  The first dose of Hu5F9-G4 
(priming dose) and must be given within 30 days of all Screening assessments. 
7.3. 
Study Procedures 
Refer to the schedules provided in Table 7-1, Table 7-2, Table 7-3, and Table 7-4 for 
specific timing of study procedures. 
7.3.1. 
Physical Examination 
Physical examinations will be assessed in accordance with the schedules provided 
in Section 7 (Table 7-1, Table 7-2, and Table 7-3).  A complete physical examination 
should be performed at Screening.  Thereafter, symptom-directed physical 
examinations are acceptable.  Changes from baseline abnormalities should be 
recorded in the patient’s study source documents.  New or worsened abnormalities 
should be recorded as AEs on the Adverse Event Case Report Form (CRF). 
Height should be recorded during Screening only; weight should be recorded during 
Screening and on Day 1 of each cycle.  Refer to Section 6.1.1 for guidelines 
regarding weight-based dosing for Hu5F9-G4. 


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7.3.2. 
Vital Signs 
Vital signs will be assessed in accordance with the schedules provided in Section 7 
(Table 7-1, Table 7-2, and Table 7-3).  Vital signs should include heart rate, 
respiratory rate, blood pressure, and temperature, and weight. 
7.3.3. 
Electrocardiograms 
Electrocardiograms (ECGs) will be assessed in all patients in accordance with the 
schedule provided in Table 7-1.  One ECG will be performed at Screening.  
Triplicate ECGs will be performed at the visits indicated after Screening.  
If applicable, the triplicate ECGs should be performed within 2 hours prior to the first 
infusion (i.e., Hu5F9-G4 on C1D1, avelumab on C1D8 and C2D1) and within 
30 minutes of the end of Hu5F9-G4 infusion on treatment.  The interval between 
ECG reads will be according to the Institution’s standard of care. 
7.3.4. 
Eastern Cooperative Oncology Group Performance Status 
ECOG performance status will be assessed in all patients in accordance with the 
schedules provided in Section 7 (Table 7-1, Table 7-2, and Table 7-3).  The ECOG 
performance status scale is provided in Appendix D. 
The ECOG performance status is a scale used to assess how a patient's disease is 
progressing, assess how the disease affects the daily living abilities of the patient, 
and determine appropriate treatment and prognosis. 
7.3.5. 
Pregnancy Test 
Pregnancy tests will be performed in accordance with the schedules provided in 
Section 7 (Table 7-1, Table 7-2).  Pregnancy tests are required only for women of 
childbearing potential.  Note that a woman is considered to be of childbearing 
potential (WOCBP), i.e., fertile, following menarche and until becoming post-
menopausal unless permanently sterile.  Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.  
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  A high follicle stimulating hormone (FSH) level in the 


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postmenopausal range may be used to confirm a post-menopausal state in women 
not using hormonal contraception or hormonal replacement therapy.  However, in 
the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.  
A urine or serum pregnancy test is required at Screening and within 72 hours before 
study drug administration on Day 1.  The Day 1 pregnancy test does not need to be 
repeated if the Screening pregnancy test was performed within the 72 hours before 
study drug administration.  Pregnancy tests will be performed every 4 weeks, 
starting with Cycle 2. 
7.3.6. 
Laboratory Tests 
Laboratory assessments will be performed in accordance with the schedules 
provided in Section 7 (Table 7-1, Table 7-2, and Table 7-3).  Most laboratory 
assessments will be performed locally at each study center’s laboratory by means of 
their established methods; analytes to be assessed by the local laboratory or 
specialty laboratories are presented in Table 7-5.  Before starting the study, the 
Investigator will provide the Sponsor (or designee) with a list of the normal ranges 
and units of measurement.  Pre-infusion assessments may be performed up to 
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Table 7-5. 
Analyte Listing 
Chemistry 
Hematology 
Urinalysis 
Type and Screen 
(ABO/Rh), 
Direct Antiglobulin Test 
Other Laboratory 
Measurements 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Total protein 
Albumin 
Calcium 
Magnesium 
Phosphorus 
Glucose 
BUN or Urea 
Creatinine 
Uric acid 
Phosphorus 
Total bilirubin 
Direct bilirubin 
LDH 
AST (SGOT) 
ALT (SGPT) 
Alkaline 
phosphatase 
RBC 
Hemoglobin 
Hematocrit 
Platelets 
WBC Differential 
• Neutrophils 
• Eosinophils 
• Basophils 
• Lymphocytes 
• Monocytes 
Reticulocytes 
Haptoglobin 
D-Dimer 
Thrombin 
Plasma fibrinogen 
PT, aPTT, and INR  
Peripheral Blood Smear 
• Spherocytes 
• RBC Fragments/Schistocytes 
• RBC Agglutination 
• Nucleated RBCs 
• RBC abnormalities 
• Platelet Aggregation 
RBC 
Glucose 
Protein  
Urine pH  
Ketones  
Bilirubin  
Urine 
specific gravity 
Blood 
ABO 
Rh Blood Group System 
• Rh D Factor 
• Rh C Factor 
• Rh E Factor 
• Rh c Factor 
• Rh e Factor 
Kell Antigen 
Kidd Antigen 
Duffy Antigen  
MNS Blood Group 
• M +/- 
• N +/- 
• S +/- 
• s +/- 
DAT 
Serum or Urine 
Pregnancy 
  
Pharmacokinetics a 
ADAs a 
ACTH/FSH/TSH/ 
T3 (Total)/T4 (Free) 
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Abbreviations:  ABO = any of the four blood groups A, B, AB, and O comprising the ABO system; ACTH = adrenocorticotropic hormone; 
ADA = anti-drug antibody; ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate aminotransferase; 
BUN = blood urea nitrogen; DAT = direct antiglobulin test; FSH = follicle-stimulating hormone; INR = international normalized ratio; 
LDH = lactate dehydrogenase; PT = prothrombin time; RBC = red blood cell; Rh = Rhesus factor; SGOT = serum glutamic oxaloacetic 
transaminase; SGPT = serum glutamic pyruvic transaminase; T3 = triiodothyronine; T4 = thyroxine; TSH =  thyroid-stimulating hormone; 
WBC = white blood cells. 
Note:  Refer to Section 7.1 Schedule of Assessment tables for collection time points. 
a. These assays may be performed at a specialty laboratory. 
 


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7.3.6.1. 
Serum Chemistry 
Serum chemistries will be assessed at the time points outlined in the schedules 
provided in Section 7 (Table 7-1, Table 7-2, and Table 7-3).  Analytes to be 
assessed by the local laboratory or specialty laboratories are presented in Table 7-5. 
7.3.6.2. 
Complete Blood Count with Differential 
CBC with differential will be assessed at the time points outlined in the schedules 
provided in Section 7 (Table 7-1, Table 7-2, and Table 7-3).  CBC will include WBC 
count with five-part differential (neutrophils, lymphocytes, monocytes, eosinophils, 
and basophils), RBC count, platelet count, hemoglobin, and hematocrit.  Specific 
hematology tests to be assessed by the local laboratory or specialty laboratories are 
presented in Table 7-5. 
7.3.6.3. 
Peripheral Blood Smear Assessment 
Peripheral smears will be collected at selected time points as outlined in the 
schedule provided in Table 7-1 and Table 7-2, and assessed for the presence of 
hemagglutination, in addition to standard cell morphology assessment.  Slides 
should be processed and assessments occur in accordance with your local practice.  
These samples should be collected from the arm contralateral to the arm being used 
for drug infusion, if possible.  Whenever possible, peripheral smears will be 
evaluated according to the guidelines provided in Appendix E.  For patients 
undergoing blood transfusion, samples for peripheral smears will be collected 1 hour 
(± 30 minutes) after completion of the transfusion.  
 
 
 
7.3.6.4. 
Serum Uric Acid and Phosphorus 
Serum uric acid and phosphorus tests will be performed at the time points outlined in 
the schedule provided in Table 7-1 and Table 7-2. 
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7.3.6.5. 
Haptoglobin, D-dimer, Thrombin Time, and Plasma Fibrinogen 
Haptoglobin, D-dimer, thrombin time, and plasma fibrinogen tests will be performed 
at the time points outlined in the schedule provided in Table 7-1 and Table 7-2. 
7.3.6.6. 
Prothrombin Time/ International Normalized Ratio, Activated 
Partial Thromboplastin Time 
Prothrombin time/ international normalized ratio, and activated partial thromboplastin 
time (PT/INR, aPTT) will be assessed at the time points outlined in the schedule 
provided in Table 7-1 and Table 7-2. 
7.3.6.7. 
Type and Screen (ABO/Rh), Direct Antiglobulin Test 
Due to the risk of developing anemia, blood phenotyping, type and screen 
(ABO/Rh), and DAT should be performed at Screening prior to exposure to 
Hu5F9-G4:  Full phenotyping (if not transfused in last 3 months) should include 
ABO, Rh, D, C, E, Kell, Kidd, Duffy, MNS, and antibody screen tests.  (The complete 
list of analytes is presented in Table 7-5.)  Treatment with Hu5F9-G4 may make 
phenotyping difficult due to expected coating of the RBC membrane.  In addition, 
patients who experience a drop in hemoglobin to below 9 g/dL at any time, or 
patients in whom clinical findings indicate a possible need for transfusions, it is 
recommended, but not required, that a Type and Screen, and DAT, be performed. 
7.3.7. 
Urinalysis 
Urinalysis will be assessed at the time points outlined in the schedule provided in 
Table 7-1 and Table 7-2.  Urinalysis will include dipstick results for color, 
appearance, specific gravity, pH, RBCs, glucose, bilirubin, ketones, occult blood, 
and protein. 
7.3.8. 
Pharmacokinetic Assessments 
Serum samples for PK analysis will be collected according to the schedules provided 
in Section 7 (Table 7-1, Table 7-2, Table 7-3, and Table 7-4).  PK samples will be 
collected to assess the PK of Hu5F9-G4 and to explore the kinetics of avelumab.  
PK samples will be sent to a central lab for processing.  The exact date and time of 


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each PK sampling should be recorded, as well as the exact date and time of the 
beginning and end of each infusion of Hu5F9-G4 and avelumab.  Samples should be 
drawn on the contralateral arm from where the study drugs are being infused and 
they should not be drawn from central lines where the relevant study drugs have 
been previously infused. 
7.3.9. 
 Biomarker Assessments 
 
 
 
 
 
 
 
  
 
 
7.3.10. 
Anti-drug Antibodies 
ADAs will be tested according to the schedules provided in Section 7 (Table 7-1, 
Table 7-2, and Table 7-3).  As shown in the SOA Table 7-1 and Table 7-2, 
peripheral blood for immunogenicity assessments for ADAs against Hu5F9-G4 
 will be collected on Days 1, and then on Day 1 of Cycles 2 to 4, and 
every 3 cycles thereafter to coincide with tumor response assessments, and as 
shown in Table 7-3, at the End of Treatment and Safety Follow-up Visits.  When 
collected on the day of study drug dosing, the blood sample must be collected 
before dose administration.  A validated tiered testing process 
(screening+confirmation+titre) will be used to measure antibodies to Hu5F9-G4 in 
serum samples.  For patients who have tested positive for ADAs, the impact of 
ADAs on PK, safety, and biologic activity may be assessed, if relevant.  
 
 
 
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7.3.11. 
Tumor Biopsies 
Biopsies will be collected according to the schedules provided in Section 7 
(Table 7-1, Table 7-2, and Table 7-3).  Tumor biopsies will be used to explore the 
effects of Hu5F9-G4 and avelumab on the tumor microenvironment, including but 
not limited to, the possible evaluation of the types of immune cells present and the 
expression of CD47 and other relevant markers.  In addition, PD-L1 expression will 
be evaluated on tumor cells and/or immune cells by immunohistochemistry.  These 
tumor biopsies are 
 mandatory in Part 2, 
unless the Investigator and Sponsor determine that, in particular cases, obtaining a 
tumor biopsy is not feasible.  These reasons could include, but are not limited to, 
lack of accessible tumor tissue to biopsy and patient safety issues.  A tumor biopsy 
will be collected during the Screening Period prior to first dose and on Cycle 3 Day 1 
(± 2 weeks).  Core biopsies may be collected for these time points; however 
excisional biopsies, where possible, are preferred over core biopsies.  Fine needle 
aspiration biopsies are not acceptable.  Biopsies should ideally contain 30% or 
≥100 viable tumor cells. 
 
 
 
7.3.12. 
Response Assessments 
Response assessments will be collected according to the schedules provided in 
Section 7 (Table 7-1, Table 7-2, and Table 7-3).  Appropriate cancer staging 
assessments should be performed.  Imaging assessments are to be conducted 
according to RECIST v1.1 (Eisenhauer 2009) and irRECIST (Bohnsack 2014) as 
described in Section 10.1.  The same imaging modality used at Screening should be 
used throughout the study whenever possible. 
The first response assessment will occur at Cycle 3, Day 1 (± 1 week).  
After Cycle 3, assessments will have a window of ±2 weeks.  Subsequent response 
assessments will occur every 2 cycles.  Response assessment will be obtained at 
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treatment termination, unless a prior radiographic assessment was performed within 
the past 4 weeks or a prior response assessment showed documented confirmed 
PD.  Tumor markers should be obtained at Screening (Section 7.3.11).  If applicable, 
they should be obtained on Day 1 of Cycles 2, 3, and 4.  From Cycle 5 and onward, 
they may be obtained every 2 cycles. 
7.3.13. 
Adverse Events 
Adverse events will be recorded according to the schedules provided in Section 7 
(Table 7-1, Table 7-2, Table 7-3, and Table 7-4).  After signing informed consent, all 
SAEs will be collected regardless of attribution (Section 9.2.1).  At each visit all AEs 
observed by the Investigator or reported by the patient that occur after the first dose 
of study drug through 30 days after the last dose of study drug are to be reported 
using the applicable electronic case report form (eCRF; Section 9.3.1).  AEs that 
occur prior to study treatment that are assessed as related to a protocol-mandated 
intervention (e.g., invasive procedures such as biopsies) must also be reported. 
Following 30 days after the last dose of study drug, Investigators are to report any 
new study drug-related SAEs that occur up to 90 days after the last dose or the start 
of new anti-cancer treatment (whichever occurs first), any ongoing SAEs, and study 
drug-related AEs, including late-onset immune-mediated AEs.  At any time, any new 
SAEs assessed by the Investigator as related to Hu5F9-G4 and/or avelumab must 
be reported.  Patients who develop study drug-related AEs or SAEs within the 
90-day period will be seen by the study physician. 
7.3.14. 
Concomitant Medications 
Concomitant medications will be recorded according to the schedules provided in 
Section 7 (Table 7-1, Table 7-2, Table 7-3, and Table 7-4).  All concomitant 
medications taken by a patient while on study are to be documented.  Changes in 
baseline concomitant medication information is to be collected after consent through 
the end of the 30-day Safety Follow-up Period.  Concomitant medications associated 
with procedure-related AEs will be captured from the time of informed consent on.  


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Information to be collected includes therapy name, indication, dose, unit, frequency, 
route, start date, and stop date, and is to be reported using the applicable eCRF. 
7.3.15. 
End of Treatment Visit 
The End of Treatment (EOT) Visit to be completed within 14 days of the decision to 
end treatment with either or both study drugs.  Refer to the schedule provided in 
Table 7-3 for specific EOT study procedures. 
7.3.16. 
Safety Follow-up 
The Safety Follow-up Visit is to be completed within 30 days (± 1 week) after the last 
dose of the last study drug received.  Refer to the schedule provided in Table 7-3 for 
specific Safety Follow-up Visit procedures.  Patients will be followed until PD or until 
they begin a new anti-cancer therapy.  For patients who achieve a PR or CR while 
on study, a repeat disease assessment will be obtained at the time of PD whenever 
possible.  
 
The Safety Follow-up Contact is to be completed by phone 90 days (± 5 days) after 
the last dose of last study drug received.  The call will collect information on new 
study drug-related SAEs, ongoing SAEs, and study drug-related non-serious AEs, 
including late-onset immune-mediated AEs.  At any time, any new SAEs assessed 
by the Investigator as related to Hu5F9-G4 and/or avelumab must be reported.  
Patients who develop study drug-related AEs or SAEs within the 90-day period will 
be seen by the study physician. 
7.3.17. 
Long-term Follow-up 
After the Safety Follow-up Contact (90 days after last dose), patients will be followed 
for any ongoing SAEs and study drug-related AEs and new SAEs assessed as 
related to study drug every 4 weeks until resolution to baseline, stabilization, until the 
patient starts a new anti-cancer therapy, or the patient is lost to follow-up, whichever 
occurs first.  Any SAE assessed as related to study drug must be reported whenever 
it occurs, irrespective of the time elapsed since the last administration of study drug.  
Patients will also be asked about any anti-cancer therapy.  For patients without 
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documentation of disease progression, long-term follow-up will occur every 8 weeks 
until disease progression or the patient begins a new anti-cancer therapy. 
7.3.18. 
Survival Follow-up 
Survival will be assessed in accordance with the schedule provided in Table 7-3.  
All patients who permanently discontinue all study treatment will be contacted during 
a clinic visit or by telephone to assess the following: 
• Survival 
• Disease progression (if not documented previously) 
• Commencement of new cancer therapy following the last administration of 
study drug 
Patients will be contacted every 3 months (± 1 month) from the date of the Safety 
Follow-up Contact, until 60 months from the date that the last patient is enrolled into 
the study or full withdrawal of consent until death or study closure, whichever occurs 
first.  For any patient who dies during this period, the date and cause of death must 
be reported to the Sponsor.  The patient’s primary physician or family may be 
contacted by the investigator to obtain survival information in case the patient cannot 
be reached. 
8. STUDY DISCONTINUATION 
8.1. 
Withdrawal of Patients from Study Drug Treatment 
Patients (or a legally acceptable representative) may decline to continue receiving 
study drug at any time during the study.  The patient’s health and welfare is the 
primary consideration in any determination to discontinue study drug treatment.  
Patients who withdraw from study drug during the treatment period should be 
encouraged to return for an EOT Visit for evaluation of safety within 2 weeks of the 
decision to end Hu5F9-G4 + avelumab combination treatment.  The studies to be 
performed at this visit are listed in Schedule of Assessments Table 7-3.  It is strongly 
encouraged that patients return for their Safety Follow-up Visit 30 days (± 1 week) 
after their last dose of study drug.  The assessments to be performed at this visit are 


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described in Table 7-3.  All patients who withdraw from study drug treatment will be 
followed for disease response and survival. 
Reasons for withdrawal from study drug treatment may include, but are not limited 
to:  
• Confirmed tumor progression according to irRECIST. 
• Unacceptable toxicity. 
• Clinically significant change in the patient’s status that precludes further 
treatment (e.g., pregnancy or other AE), after discussion with the Medical 
Monitor. 
• Patient’s request, with or without a stated reason.  In case the patient decides 
to withdraw from treatment, further study assessments should be performed 
unless declined by the patient. 
• Investigator or treating physician decision in the absence of any of the above. 
• Pregnancy. 
8.2. 
Withdrawal of Patients from Study 
Patients have the right to withdraw from the study at any time and for any reason 
without prejudice to his or her future medical care.  Patients (or a legally acceptable 
representative) may decline to continue receiving study drug and/or other 
protocol-required therapies or procedures at any time during the study.  Patient data 
up to withdrawal of consent will be included in the analysis of the study and, where 
permitted, publicly available data may be included after withdrawal of consent.  
The Investigator is to discuss with the patient the appropriate procedures for 
withdrawal from the study.  The Investigator or Sponsor has the right to discontinue 
any patient from study participation. 
Reasons for patient withdrawal from the study may include, but are not limited to: 
• Death 
• Withdrawal of consent 
• Lost to follow up 
• Study termination 


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8.3. 
Defining the End of Study 
The end of the study for all patients occurs at the primary completion date, which is 
defined as the date on which the last patient completes the last visit (phone contact 
is also considered as a visit) or when the CTSC decides to terminate the study, 
whichever occurs first. 
Recruitment will cease when one of the following occurs: 
• Study treatment is considered too toxic to continue treatment before the 
anticipated number of patients are recruited.  This assessment will be made 
by the CTSC. 
• The stated number of patients to be recruited is reached.  This number may 
be increased to include replacement patients for those who are not 
DLT-evaluable and patients added to intermediate dose or expanded cohorts 
as determined by the CTSC, and approved, if necessary, by the appropriate 
IRBs. 
• The stated objectives of the trial are achieved. 
• Sponsor decision. 
In terminating the study, the Sponsor and the Investigators must ensure that 
adequate consideration is given to the protection of the patient’s interest. 
8.4. 
Study Termination 
The Sponsor reserves the right to terminate the study at any time.  Both the Sponsor 
and the Investigator reserve the right to terminate the Investigator’s participation in 
the study according to the study contract.  The Investigator is to notify the 
IRB/Independent Ethics Committee (IEC) in writing of the study’s completion or the 
Investigator’s termination of participation in the study and send a copy of the 
notification to the Sponsor. 


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9. ASSESSMENT OF SAFETY 
9.1. 
Safety Parameters and Definitions 
Safety assessments will consist of recording all AEs and SAEs; protocol-specified 
hematology and clinical chemistry variables; measurement of protocol-specified vital 
signs; and the results from other protocol-specified tests that are deemed critical to 
the safety evaluation of the combination of these study drugs. 
The Sponsor, or its designee, is responsible for reporting relevant SAEs to the 
Competent Authority, other applicable regulatory authorities, and participating 
Investigators, in accordance with International Conference on Harmonisation (ICH) 
guidelines, FDA regulations, European Clinical Trials Directive, and/or local 
regulatory requirements. 
9.1.1. 
Adverse Event 
An AE is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of an investigational product or other protocol-imposed 
intervention, regardless of attribution. 
This includes the following: 
• AEs not previously observed in the patient that emerge during the 
protocol-specified AE reporting period. 
• Complications that occur as a result of protocol-mandated interventions 
(e.g., invasive procedures such as biopsies), including AEs that occur prior to 
study drug treatment that are related to protocol-mandated interventions. 
• Events that occur prior to administration of both study drugs that are related 
to a protocol-mandated intervention (e.g., invasive procedures such as 
biopsies) 
• Pre-existing medical conditions, judged by the Investigator to have worsened 
in severity or frequency or changed in character during the protocol-specified 
AE reporting period. 


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9.1.2. 
Serious Adverse Event 
An SAE is any AE that at any dose is: 
• Fatal (i.e., the AE is the actual cause of death) 
• Life-threatening (i.e., the AE, in which the patient was at immediate risk of 
death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe)  
• Requires or prolongs inpatient hospitalization 
• Results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the patient’s ability to conduct normal life functions) 
• A congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to the study drug(s) 
• Considered a significant medical event by the Investigator based on sound 
medical and scientific judgment (i.e., may jeopardize the patient or may 
require medical/surgical intervention to prevent one of the outcomes listed 
above) 
All AEs that do not meet any of the criteria for serious should be regarded as 
non-serious AEs. 
The terms “severe” and “serious” are not synonymous.  Severity refers to the 
intensity of an AE (as in Grade 1 [mild], Grade 2 [moderate], Grade 3 [severe], 
Grade 4 [life-threatening] or Grade 5 [death] according to CTCAE v. 4.03).  
The event itself may be of relatively minor medical significance (such as severe 
headache).  “Serious” is a regulatory definition and is based on patient or event 
outcome or action criteria usually associated with events that pose a threat to a 
patient’s life or vital functions.  Seriousness (not severity) serves as the guide for 
defining regulatory reporting obligations. 
Severity and seriousness should be independently assessed when recording AEs 
and SAEs. 


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9.2. 
Methods and Timing for Capturing and Assessing Safety Parameters 
The Investigator is responsible for ensuring that all AEs and SAEs are recorded on 
the eCRF and that SAEs are recorded on the SAE Report Form and reported to the 
Sponsor in accordance with instructions in the Study Reference Manual.  SAEs must 
be reported to the Sponsor or designee within 24 hours of the Investigator becoming 
aware of the event. 
9.2.1. 
Adverse Event Reporting Period 
After signing of informed consent, but prior to initiation of any of the study drugs, all 
events deemed by the Investigator to have been caused by a protocol-mandated 
intervention (e.g., invasive procedures such as biopsies) will be collected as AEs 
(or SAEs if any of the serious criteria apply). 
After initiation of any of the study drugs, all AEs and SAEs, regardless of attribution, 
will be collected until 30 days following the last administration of last study drug 
received, or until the Safety Follow-up Visit (whichever occurs later) unless the 
patient begins a new anti-cancer therapy before that. Until 90 days after the last 
dose of last study drug received or the Safety Follow-up Contact (whichever occurs 
later), Investigators are to report only new study drug-related AEs or SAEs, 
(including late-onset immune-mediated AEs).  Patients who develop study 
drug-related AEs or SAEs within the 90-day period will be seen by the study 
physician.  Follow-up information regarding SAEs and study drug-related AEs will be 
reported until resolution (or return to baseline), stabilization of the event, the patient 
is lost to follow-up or withdraws consent, the Medical Monitor deems it necessary, or 
the patient initiates new anti-cancer therapy, whichever occurs first.  Follow-up will 
be conducted as described in Section 7.3.16 and Section 7.3.17.  Resolution of AEs 
and SAEs (with dates) should be documented on the Adverse Event eCRF, on the 
SAE Report Form (if applicable), and in the patient’s medical record to facilitate 
source data verification.  The Sponsor or its designee may follow up by telephone, 
fax, electronic mail, and/or a monitoring visit to obtain additional case details 


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(e.g., hospital discharge summary, consultant report, or autopsy report) deemed 
necessary to appropriately evaluate the SAE report. 
At any time, Investigators are to report SAEs that they assess to be related to any of 
the study drugs (Hu5F9-G4 and/or avelumab received as part of this study). 
9.2.2. 
Eliciting Adverse Events 
A consistent method of non-directive questioning for eliciting AEs at all patient 
evaluation time points should be adopted.  Examples of non-directive questions 
include: 
“How have you felt since your last clinic visit?” 
“Have you had any new or changed health problems since you were last 
here?” 
 
9.2.3. 
Assessment of Severity and Causality of Adverse Events 
Investigators will seek information on AEs and SAEs at each patient contact.  
All AEs and SAEs, whether reported by the patient or noted by authorized study 
personnel, will be recorded in the patient’s medical record and on the Adverse Event 
eCRF, and on the SAE report form, if applicable. 
For each AE and SAE, the Investigator will make an assessment of seriousness 
(Section 9.1.2), severity (Table 9-1), and causality (Table 9-2).  A causality 
assessment will be made for both Hu5F9-G4 and avelumab individually.  Table 9-2 
provides guidance for assessing the causal relationship to study drug(s). 
The AE grading (severity) scale NCI CTCAE Version 4.03 (Appendix C) will be used 
for AE reporting as shown in Table 9-1.  As described in Section 6.5 (Safety 
Management Guidelines), customized severity grading for hemagglutination and 
microangiopathy AEs will be used (Appendix C). 


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Table 9-1. 
Adverse Event Grade (Severity) Scale 
Grade 
Severity 
Alternate Description a 
1 
Mild; asymptomatic or mild 
symptoms; clinical or diagnostic 
observations only; intervention 
not indicated. 
Transient or mild discomfort (<48 hours); 
no interference with the patient’s daily 
activities; no medical intervention/therapy 
required 
2 
Moderate; minimal, local or 
noninvasive intervention 
indicated; limiting 
age-appropriate instrumental 
ADLa. 
Mild-to-moderate interference with the 
patient’s daily activities; no or minimal 
medical intervention/therapy required 
3 
Severe (apply event-specific  
NCI CTCAE grading criteria) 
Severe or medically significant 
but not immediately 
life-threatening; 
hospitalization or prolongation 
of hospitalization indicated; 
disabling; limiting self care 
ADLb. 
Considerable interference with the patient’s 
daily activities; medical intervention/therapy 
required; hospitalization possible 
4 
Life-threatening consequences; 
urgent intervention indicated. 
Extreme limitation in activity; significant 
medical intervention/therapy required, 
hospitalization probable 
5 
Death related to adverse event 
 
Abbreviations:  ADL = activities of daily living; AE = adverse event; NCI CTCAE = National 
Cancer Institute Common Terminology Criteria for Adverse Events. 
Source:  NCI CTCAE, Version 4.03 (Appendix C) 
Notes:  Use the alternate descriptions for Grade 1, 2, 3, and 4 events when the observed or 
reported AE does not appear in the NCI CTCAE listing.  A Semi-colon indicates ‘or’ within the 
description of the grade.  A single dash (-) indicates a grade is not available. 
a. Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
b. Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
To ensure consistency of causality assessments for either study drug, Investigators 
should apply the following general guidelines (Table 9-2). 


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Table 9-2. 
Causal Attribution Guidance 
Is the AE/SAE suspected to be caused by the investigational product based on 
facts, evidence, science-based rationales, and clinical judgment? 
YES = 
Related 
The temporal relationship of the AE/SAE to investigational product 
administration makes a causal relationship possible, AND other drugs, 
therapeutic interventions or underlying conditions do not provide sufficient 
explanation for the AE/SAE. 
NO = 
Not 
Related 
The temporal relationship of the AE/SAE to investigational product 
administration makes a causal relationship unlikely, OR other drugs, 
therapeutic interventions or underlying conditions provide a sufficient 
explanation for the AE/SAE. 
Abbreviations:  AE = adverse event; SAE = serious adverse event. 
Note:  The Investigator’s assessment of causality for individual AE reports is part of the study 
documentation process.  Regardless of the “Related” or “Not Related” causality assessment for 
individual AE reports, the Sponsor or its designee, will promptly evaluate all reported SAEs against 
cumulative product experience to identify and expeditiously communicate possible new safety 
findings to Investigators and applicable regulatory authorities. 
 
9.3. 
Procedures for Recording Adverse Events 
9.3.1. 
Recording Adverse Events 
Investigators should use correct medical terminology and concepts when recording 
AEs and SAEs.  Colloquialisms and abbreviations are to be avoided. 
A separate log line in the AE eCRF should be used for each medical concept that 
needs to be recorded. 
9.3.1.1. 
Diagnosis Versus Signs and Symptoms 
If known, a diagnosis should be recorded rather than individual signs and symptoms 
(e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases).  However, if a constellation of signs and/or symptoms cannot be 
medically characterized as a single diagnosis or syndrome at the time of reporting, 
each individual event should be recorded as an AE on separate log lines of the 
eCRF and SAE report form (if the event is serious).  If a diagnosis is subsequently 
established, it should be reported to the Sponsor by subsuming the symptoms under 
the reported diagnosis, in accordance with the CRF Completion Guidelines. 


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9.3.1.2. 
Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause.  For example, if severe 
diarrhea is known to have resulted in dehydration, it is sufficient to record only 
diarrhea as an AE on the eCRF.  However, medically significant AEs occurring 
secondary to an initiating event that are separated in time should be recorded as 
independent events on the eCRF.  For example, if a severe gastrointestinal 
hemorrhage leads to renal failure, both events should be recorded separately on the 
eCRF. 
9.3.1.3. 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution between patient 
evaluation time points.  Such events should only be recorded once in the eCRF 
unless their severity increases.  If a persistent AE increases or decreases in 
severity, it should be recorded again on a new log line on the Adverse Event eCRF 
indicating the change in severity. 
A recurrent AE is one that occurs and resolves between patient evaluation time 
points and subsequently recurs.  All recurrent AEs should be recorded on Adverse 
Event eCRF each time they occur. 
9.3.1.4. 
Abnormal Laboratory Values 
Only clinically significant laboratory abnormalities will be recorded as AEs on 
the eCRF (e.g., abnormalities that require study drug dose modification or 
discontinuation, more frequent follow-up assessments, further diagnostic 
investigation, etc.). 
If the clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 × ULN associated with cholecystitis), only 
the diagnosis (e.g., cholecystitis) needs to be recorded on the Adverse Event eCRF. 


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If the clinically significant laboratory abnormality is not a sign of a disease or 
syndrome, the abnormality itself should be recorded as an AE on the eCRF.  If the 
laboratory abnormality can be characterized by a precise clinical term, the clinical 
term should be recorded as the AE.  For example, an elevated serum potassium 
level of 7.0 mEq/L should be recorded as “hyperkalemia.” 
Observations of the same clinically significant laboratory abnormality from visit to 
visit should not be repeatedly recorded as AEs or SAEs on the eCRF, unless their 
severity, seriousness, or etiology changes. 
9.3.1.5. 
Deaths 
All deaths that occur during the protocol-specified AE reporting period 
(Section 9.2.1), regardless of attribution, will be recorded on an eCRF and SAE 
Report Form and reported to the Sponsor within 24 hours of awareness and not later 
than the next business day.  This includes death attributed to progression of 
disease. 
If the death is attributed to progression of disease, especially in the absence of other 
signs and symptoms, record “[specific disease type] progression” as the SAE term 
on the SAE Report Form. 
When recording a death on an eCRF or SAE Report Form, the event or condition 
that caused or contributed to the fatal outcome should be recorded as the single 
medical concept whenever possible. 
9.3.1.6. 
Worsening of Disease 
Worsening of and/or progression of disease should not be routinely recorded as an 
AE or SAE if it does not result in death.  These data will be captured as efficacy 
assessment data.  However, worsening and/or progression of disease can be 
recorded as an SAE, if the outcome is fatal in the absence of other signs and 
symptoms, or if the Investigator assesses the PD to be related to one of the study 
drugs. 


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9.3.1.7. 
Hospitalization, Prolonged Hospitalization, or Surgery 
Any AE that results in hospitalization or prolonged hospitalization should be 
documented and reported as an SAE unless specifically instructed otherwise in this 
protocol. 
There are some hospitalization scenarios that do not require reporting as an SAE 
when there is no occurrence of an AE.  These scenarios include a planned 
hospitalization or prolonged hospitalization to: 
• Perform an efficacy measurement for the study 
• Undergo a diagnostic or elective surgical procedure for a pre-existing medical 
condition that has not changed 
• Receive scheduled therapy for the target disease of the study 
• Hospitalization for social reason (e.g. respite care, waiting for insurance 
authorization) 
9.3.1.8. 
Other Reportable Information 
Certain information, although not considered an AE or SAE, must be recorded, 
reported, and followed up as indicated below.  The following sections describe such 
information. 
9.3.1.8.1. 
Pregnancy 
Female patients who become pregnant during the treatment period must be 
withdrawn from study treatment immediately. 
Any pregnancy occurring in a patient or a patient’s partner during treatment with 
either study drug or within 6 months of last study drug administration must be 
reported to the Sponsor’s safety clinical research organization (CRO) (Section 9.2) 
within 24 hours of becoming aware of it, using a Pregnancy Notification Form 
(provided in the Investigator Trial File).  It is the Investigator’s responsibility to obtain 
consent for follow-up from the patient or patient’s partner.  The safety CRO will 
follow-up on all pregnancies for the pregnancy outcome through the Investigator, 
using a Pregnancy Outcome Form.  Data will be collected about the pregnancy, fetal 


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status, neonate status.  In the event that the neonate has abnormalities at birth, 
additional data will be collected for the infant about those abnormalities.  
Spontaneous or therapeutic abortion should always be reported as an SAE 
(medically significant event) and recorded on a Serious Adverse Event Report Form, 
and expeditiously reported to the Sponsor as described in Section 9.2.  Any 
congenital anomaly/birth defect in a child born to a female patient or female partner 
of a male patient exposed to any of the study drugs should also be recorded and 
reported as an SAE within 24 hours of awareness. 
9.3.1.8.2. 
Overdose 
An overdose of Hu5F9-G4 is defined as a dose higher than that indicated in the 
protocol, with or without experiencing an AE. 
An overdose of avelumab is defined as any dose ≥10% than the planned dose for 
that particular administration. 
Any overdose must be recorded in the trial drug section of the eCRF. 
9.3.1.8.3. 
Abuse or Misuse 
Abuse or misuse of a study drug is use for nonclinical reasons, with or without 
experiencing an AE. 
9.4. 
Reporting Requirements for Serious Adverse Events 
Investigators will submit reports of all SAEs, regardless of attribution, within 24 hours 
of awareness according to the instructions provided by the Sponsor. 
Medical Monitor Contact Information for Sites: 
 
Telephone No.:  
 
Alternate Telephone No.:  
 
Email:  
 
PPD
PPD
PPD
PPD


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Alternate Medical Monitor Contact Information for Sites: 
 
Telephone No.:  
 
Alternate Telephone No.:  
 
Email:  
 
 
10. MEASUREMENT OF EFFECT 
10.1. Anti-Cancer Effect 
Patients will be assessed for response using RECIST v1.1 (Eisenhauer 2009) for the 
primary efficacy endpoint and irRECIST (Bohnsack 2014) for the secondary efficacy 
endpoint.  The first response assessment will occur after 2 cycles of treatment.  
Subsequent response assessments will occur every 2 cycles or approximately 
8 weeks.  Tumor markers will be obtained, as appropriate, at baseline, and then 
every cycle until Cycle 5, then every 2 cycles.  Finally, response assessment will be 
obtained at the EOT Visit, unless a prior radiographic assessment has been 
performed within the last 4 weeks or a prior response assessment documented 
confirmed PD. 
11. STATISTICAL CONSIDERATIONS 
The primary objectives of this Phase 1b study are to describe the safety and 
tolerability of the combination of Hu5F9-G4 and avelumab and determine the 
recommended Phase 2 dose and schedule (RP2DS).  As such, the statistical 
analysis will be primarily descriptive providing listings, graphic displays, frequencies, 
and/or percentages for discrete variables and the mean, standard deviation, median, 
and ranges for continuous variables.  Where relevant, 95% confidence intervals 
(CIs) may also be provided.  Time-to-event endpoints will be summarized using 
Kaplan-Meier methods. 
PPD
PPD
PPD
PPD


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11.1. Analysis Sets 
11.1.1. 
Part 1 Safety Run-In Cohort 
Dose Evaluation Set (DES) 
The Dose Evaluation Set includes all enrolled solid tumor patients in Part 1 who 
receive at least 1 dose of both Hu5F9-G4 (at a maintenance level) and avelumab 
and either experience a DLT or complete at least 4 infusions of Hu5F9-G4 (at the 
maintenance level) and 2 infusions of avelumab. 
Patients who withdraw before completing the 5-week DLT assessment period for 
reasons other than a DLT, or who do not fulfill either of the criteria above, will not be 
evaluable for dose review decisions and will be replaced in the cohort. 
11.1.2. 
Parts 1 and 2 Safety and Efficacy Analysis Cohort 
Efficacy Analysis Set (EAS) 
The Efficacy Analysis Set (EAS) includes all enrolled patients who receive at least 
4 doses of Hu5F9-G4 (at the maintenance level) and 2 doses of avelumab, and for 
whom a baseline and post-treatment tumor assessment is available. 
The analysis of overall response rate (ORR), best overall response (BOR), duration 
of response (DOR), time to tumor progression (TTP), PFS, and OS will be performed 
on the EAS. 
Safety Analysis Set (SAS) 
The Safety Analysis Set (SAS) includes all enrolled patients who receive at least 
1 dose of either study drug.  The analysis of safety will be performed on the SAS. 
PK Analysis Set (PAS) 
The PK Analysis Set (PAS) includes all patients in the SAS from whom PK blood 
samples are collected during the study and who have at least one measurable 
concentration of Hu5F9-G4. 


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11.2. Sample Size Determination 
This trial will include a total of up to 40 patients.  This sample size includes both 
Parts 1 and 2 of the study, allowing for patient replacement as defined in this 
protocol.  In Part 1, up to 12-18 patients will be treated in a Safety Run-in Cohort, 
assuming that no more than 2 DLTs in each cohort of 6 patients occur.  Up to 
18 patients may be enrolled in Part 1 if some patients are ineligible for DLT 
assessment. 
Part 2 consists of a single expansion cohort in 20 ovarian cancer patients who will 
undergo safety, PK, 
.  This sample size will allow 
for confirmation of the safety profile of Hu5F9-G4 and avelumab in this population, 
and the mandatory tumor biopsies 
 
  The anti-tumor activity of this regimen will also be documented.  With this 
sample size, the lower bound of the 95% exact CI would exclude 10% if the 
objective response rate is 30% or higher. 
11.3. Clinical Trial Steering Committee 
The CTSC will oversee the conduct of the clinical trial.  A representative from the 
Sponsor, usually the Study Medical Monitor or designee, will chair the CTSC.  
The CTSC will have representation from each participating site in the study.  
The CTSC will review safety and efficacy data generated during the trial and make 
decisions about patient recruitment, trial management, initiation of protocol specific 
amendments, expansion of cohorts, using higher or lower dose levels, defining any 
new dose cohorts, identification of the recommended dose for Part 2 
 
.  The CTSC will meet at a minimum at the completion of the DLT period for 
each cohort in the Safety Run-in part of the trial, at any protocol-specified formal 
interim analyses, and when emergent critical safety data are reported.  
The composition, structure, and function of the CTSC are defined in the 
CTSC Charter. 
CCI
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CCI


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11.4. Data Monitoring Committee 
Data Monitoring Committee functions for this trial will be performed by the CTSC, as 
defined and described in Section 11.3. 
11.5. Analysis of the Conduct of the Study 
The CTSC, in conjunction with the Sponsor, will be the main body responsible for 
the analysis of the conduct of the study, as outlined in the CTSC charter. 
11.6. Statistical Methods 
All analyses will be descriptive and hypothesis generating in nature.  Descriptive 
statistics will be provided for all safety and efficacy endpoints. 
All analyses will be conducted separately for patients in Parts 1 and 2 of the study 
unless otherwise specified.  Safety analyses may be conducted for patients in both 
Parts 1 and 2 of the study together.  Efficacy analyses may also be conducted on all 
efficacy-evaluable ovarian cancer patients. 
For continuous variables, the mean, standard deviation, median, and ranges will be 
provided.  For categorical variables, the frequency and percentage in each category 
will be provided along with 95% Clopper-Pearson CIs for primary and secondary 
efficacy endpoints.  For time-to-event variables, the Kaplan-Meier (KM) estimates 
and corresponding two-sided 95% Clopper-Pearson CIs for the median and quartiles 
will be provided.  The KM plot may also be provided.  Details regarding the statistical 
analysis to be conducted, including the handling of missing data and patient 
withdrawal, will be provided in the statistical analysis plan (SAP). 
11.6.1. 
Efficacy Analyses 
The efficacy analyses will be conducted for patients in the EAS, unless otherwise 
indicated.  The EAS will be used to analyze the outcome measures described in the 
table below. 


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Measure 
Definition 
ORR 
The proportion of patients who achieve a complete or partial response 
according to RECIST v1.1 (primary endpoint) or irRECIST (secondary 
endpoint). 
DOR 
Time from the initial response until confirmed tumor progression. 
TTP 
The length of time from first dose of treatment combination to confirmed 
tumor progression. 
PFS 
Time from first dose of treatment combination to confirmed tumor 
progression or death, whichever occurs first. 
OS 
Time from first dose of treatment combination until death. 
 
ORR will be summarized by frequency and percentages along with 95% exact CI.  
The time-to-event endpoints of DOR, TTP, PFS, and OS will be summarized using 
Kaplan-Meier methods.  Additional details will be provided in the SAP. 
11.6.2. 
Safety Analyses 
The SAS is defined as all patients who receive at least 1 dose of study drug (either 
Hu5F9-G4 or avelumab).  The statistical analysis will be descriptive, providing 
listings, graphical displays, frequencies, and percentages for discrete variables 
and/or the mean, standard deviation, median, and ranges for continuous variables.  
Safety variables to be examined include DLTs for patients in Part 1, TEAEs (AEs 
worsening or occurring during or after a patient’s first exposure to study drug), study 
drug-related adverse events (ADRs), vital signs, physical examinations, laboratory, 
CD47 RO, and ADA assessments.  AEs will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA, Version 19.0) and grouped by system organ class 
and preferred term.  Summary tables will include the number and percentage of 
patients with AEs, SAEs, fatal AEs, and other AEs of interest. 
Data will be presented by Part 1 (Safety Run-in Cohort) and by Part 2 (Ovarian 
Cancer Expansion Cohort), and, where relevant, summarized across various dose 
cohorts.  Data may be graphed, summarized, or listed depending on the amount of 
data to be reported.  Where relevant, safety data will also be presented by the study 


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day/study day interval corresponding to dose administrations within each dose 
cohort. 
11.6.2.1. 
Adverse Events 
For the SAS, AEs that occurred during Screening, but before exposure to study drug 
will be reported in the AE line listings and appropriately identified as non-TEAEs.  
Summary tables of TEAEs and ADRs will be provided using the NCI CTCAE 
Version 4.03 to describe the type and severity of event.  Peripheral smear 
assessments will be tabulated and reported separately.  TEAEs and ADRs will also 
be tabulated using Investigator assessment of the relationship to study drug (related 
or not related).  SAEs, including deaths, will be summarized and/or listed for each 
dose cohort and for all dose cohorts combined.  TEAEs and ADRs resulting in 
withdrawal from study drug or further study participation will be tabulated and/or 
listed.  DLTs will also be listed.  Unless otherwise noted, the tabulation of AEs will be 
based on patient incidence rather than event incidence. 
For patients who went through Screening only or who were enrolled but never 
treated, AEs and SAEs that occur during Screening will be reported separately as 
the "Screened-only/Never Treated” Set with line listings and/or summary tables, 
along with relevant demographic data collected. 
11.6.2.2. 
Analysis of Other Safety Endpoints 
The analysis of other safety endpoints such as vital signs, peripheral smear 
assessments, and other laboratory assessments, will include listings, graphical 
displays, and descriptive statistics such as change from baseline and/or shift tables, 
where relevant.  Details will be provided in the SAP. 
11.6.3. 
Pharmacokinetic Analyses 
PK analysis will be conducted for Hu5F9-G4 using the PAS.  Based on the distinct 
MOAs of Hu5F9-G4 and avelumab, drug-drug PK interactions are not expected.  
Thus, samples for PK analysis for avelumab will be biobanked and will be analyzed 
based on CTSC recommendation. 


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The PAS consists of all patients who have at least 1 blood sample that provides 
evaluable PK data.  The PAS will be used for summaries of PK concentration data 
and PK parameters.  Due to the sparse sampling regime, it is anticipated that the 
Cmax after the first maintenance dose will be the only calculable PK parameter in this 
population.  Individual patients may be removed from the estimation of particular PK 
parameters based on the number of available blood samples for them.  These 
patients will be identified at the time of analysis. 
Summary statistics will be presented for Hu5F9-G4 serum concentrations at each 
scheduled time point.  Descriptive graphical plots of individual serum 
concentration-versus-time profiles and mean concentration-versus-time profiles will 
be generated.  Missing concentration values will be reported as is in data listings.  
Concentration values below lower limit of quantitation will be set to zero in summary 
statistics, and reported as-is in data listings.  Any missing PK parameter data will not 
be imputed.  Population PK modelling analysis may also be conducted by combining 
Hu5F9-G4 PK data from this study along with data from other studies, but results of 
that analysis will be reported separately. 
 
 
 
 
 
 
 
11.6.5. 
Immunogenicity Analyses 
The rate and magnitude of anti-Hu5F9-G4 antibody positivity will be evaluated for all 
patients in Parts 1 and 2 of the trial, and for the pooled patient population.  The 
antibody occurrence rate will be summarized at each time point.  Titer summaries by 
time point may also be provided, if appropriate.  
 
 
 
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  Immunogenicity analysis may also be 
performed for avelumab.  However, it is not expected that Hu5F9-G4 will impact the 
immunogenicity of avelumab and vice versa. 
11.7. Handling of Missing Data 
Details regarding handling missing data will be described in the SAP. 
12. ETHICAL AND ADMINISTRATIVE CONSIDERATIONS 
12.1. Compliance Statement 
This study will be conducted in accordance with the protocol and with US FDA and 
the ICH GCP guidelines, the Declaration of Helsinki, and any applicable local health 
authority and IRB)/ IEC requirements. 
To the extent applicable, all references to the FDA, Federal Food, Drug, and 
Cosmetic Act, Code of Federal Regulations (CFR), ICH, GCP, and the like shall be 
interpreted as also referring to any corresponding requirements of local regulatory 
agencies, regulations, and laws.  If there is any discrepancy between FDA, ICH, and 
local requirements, the most stringent standard shall apply. 
12.2. Investigator Responsibilities 
As required by FDA regulation (21 CFR Part 56) and ICH guidelines for GCP, the 
Investigator at each study site must obtain IRB/IEC review and approval of the study 
protocol, ICFs, patient recruitment materials, and any other pertinent documents 
before any study-related activities involving patients are performed. 
As required in 21 CFR Part 50 and ICH guidelines for GCP, the Investigator or 
designee must comply with the informed consent process, and ensure that each 
patient enrolled in this clinical study understands the information presented in the 
IRB/IEC approved ICF and agrees voluntarily to participate in the clinical study. 
The Investigator or designee must submit to the IRB/IEC any written safety report or 
update (e.g., amended Investigator’s Brochure or safety amendments and updates) 
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provided by the Sponsor or representative, according to the IEC specific reporting 
requirements. 
The Investigator must inform the IRB/IEC of the progress of the clinical study and 
report any non-administrative changes made to the protocol; in any case, the 
Investigator must provide an update to the IRB/IEC at least once a year or in 
accordance with IRB/IEC continuing approval requirements. 
The Investigator must maintain a list of appropriately qualified persons to whom 
he/she has delegated study duties.  All persons authorized to make entries and/or 
corrections on eCRFs or other reporting forms will be included on the Forty Seven 
Inc. Delegation of Authority Form. 
The clinical study report must be signed by the Investigator or, in the case of 
multi-center studies, the Coordinating Investigator.  The Coordinating Investigator, 
identified by the Sponsor, will be any or all of the following: 
• a recognized expert in the therapeutic area. 
• an Investigator who provided significant contributions to either the design or 
interpretation of the study. 
• an Investigator contributing a high number of eligible patients. 
12.3. Institutional Review Board or Independent Ethics Committee 
A copy of the protocol, proposed ICF, other written patient information, and any 
proposed advertising material must be submitted to the IRB/IEC for written approval.  
A copy of the written approval of the protocol and ICF must be received by the 
Sponsor before recruitment of patients into the study and shipment of Hu5F9-G4. 
The Investigator must submit and, where necessary, obtain approval from the 
IRB/IEC for all subsequent protocol amendments and changes to the informed 
consent document.  The Investigator is to notify the IRB/IEC of deviations from the 
protocol or SAEs occurring at the site and other AE reports received from the 
Sponsor, in accordance with local procedures. 


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The Investigator is responsible for obtaining annual IRB/IEC approval/renewal as 
applicable throughout the duration of the study.  Copies of the Investigator’s reports 
and the IRB/IEC continuance of approval must be sent to the Sponsor. 
12.4. Informed Consent and Human Subject Protection 
An initial sample ICF is provided for the Investigator to prepare the informed consent 
document to be used at his or her site.  Updates to the template are to be 
communicated formally in writing from the Sponsor’s Study Monitor to the 
Investigator.  The written informed consent document is to be prepared in the 
language(s) of the potential patient population. 
Before a patient’s participation in the clinical study, the Investigator is responsible for 
obtaining written informed consent from the patient or legally acceptable 
representative after adequate explanation of the aims, methods, anticipated benefits, 
and potential hazards of the study and before any protocol-specific screening 
procedures or any investigational products are administered.  A legally acceptable 
representative is an individual or other body authorized under applicable law to 
consent, on behalf of a prospective patient, to the patient’s participation in the 
clinical study. 
The Investigator is also responsible for asking the patient if the patient has a primary 
care physician and if the patient agrees to have his/her primary care physician 
informed of the patient’s participation in the clinical study.  If the patient agrees to 
such notification, the Investigator is to inform the patient’s primary care physician of 
the patient’s participation in the clinical study.  If the patient does not have a primary 
care physician and the Investigator will be acting in that capacity, the Investigator is 
to document such in the patient’s medical record.  The acquisition of informed 
consent and the patient’s agreement or refusal of his/her notification of the primary 
care physician is to be documented in the patient’s medical records, and the ICF is 
to be signed and personally dated by the patient, or a legally acceptable 
representative, and by the person who conducted the informed consent discussion.  
The original signed ICF is to be retained in accordance with institutional policy, and a 


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copy of the signed consent form is to be provided to the patient or legally acceptable 
representative. 
If a potential patient is illiterate or visually impaired and does not have a legally 
acceptable representative, the Investigator must provide an impartial witness to read 
the ICF to the patient and must allow for questions.  Thereafter, both the patient and 
the witness must sign the ICF to attest that informed consent was freely given and 
understood. 
12.5. Confidentiality 
The Investigator must ensure that the patient’s confidentiality is maintained for 
documents submitted to the Sponsor, including the following: 
• Subjects are to be identified by a unique patient identification number. 
• Where permitted, date of birth is to be documented and formatted in 
accordance with local laws and regulations. 
• On the eCRF demographics page, in addition to the unique patient 
identification number, the patient’s age at time of enrollment is to be included. 
• For SAEs reported to the Sponsor, any source documentation provided 
(e.g., medical records, laboratory results) must have any patient identifier 
(e.g., patient name, initials, medical records number) fully redacted 
(i.e., blacked out) prior to transmission. 
• Documents that are not submitted to the Sponsor (e.g., signed ICFs) are to 
be kept in confidence by the Investigator, except as described below. 
In compliance with the CFR/ ICH GCP Guidelines, it is required that the Investigator 
and institution permit authorized representatives of the company, of the regulatory 
agency(s), and the IRB/IEC direct access to review the patient’s original medical 
records for verification of study-related procedures and data.  Direct access includes 
examining, analyzing, verifying, and reproducing any records and reports that are 
important to the evaluation of the study.  The Investigator is obligated to inform and 
obtain the consent of the patient to permit such individuals to have access to his/her 
study-related records, including personal information. 


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12.6. Urgent Safety Measures 
The Sponsor or Investigator may take appropriate urgent safety measures to protect 
trial participants from any immediate hazard to their health or safety.  Urgent safety 
measures may be taken without prior authorization.  The trial may continue with the 
urgent safety measures in place. 
The Investigator must inform the Sponsor IMMEDIATELY if the study site 
initiates an urgent safety measure. 
The notification must include all of the following: 
• Date of the urgent safety measure 
• Who made the decision 
• Why the action was taken 
The Investigator will provide any other information that may be required to enable 
the Sponsor to report and manage the urgent safety measure in accordance with the 
current regulatory and ethical requirements for expedited reporting and closeout. 
12.7. Serious Breaches and Fraud 
The Sponsor will comply with ICH GCP guidelines for reporting serious breaches 
and fraud which may occur in this particular trial in all regions in which the 
investigational product is being studied. 
Investigators must notify the Sponsor immediately if any serious breach of GCP is 
suspected. 
If there is any proof of fraud this must also be reported to the Sponsor.  All instances 
of confirmed clinical trial fraud occurring at sites in the United Kingdom (UK) will be 
treated according to the procedure for dealing with a serious breach and must be 
reported to the Medicines and Healthcare products Regulatory Agency (MHRA) 
within 7 days of the Sponsor becoming aware. 


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12.8. Study Monitoring 
The Sponsor’s representative(s) are responsible for contacting and visiting the 
Investigator for the purpose of inspecting the facilities and, upon request, inspecting 
the various records of the clinical study (e.g., eCRFs and other pertinent data) 
provided that patient confidentiality is respected. 
The Sponsor’s representative(s) are responsible for verifying the eCRFs at regular 
intervals throughout the study to verify adherence to the protocol; completeness, 
accuracy, and consistency of the data; and adherence to local regulations on the 
conduct of clinical research.  The Sponsor’s representative(s) are to have access to 
patient medical records and other study-related records needed to verify the entries 
on the eCRFs. 
The Investigator agrees to cooperate with the Sponsor’s representative(s) to ensure 
that any problems detected in the course of these monitoring visits, including delays 
in completing eCRFs, are resolved. 
12.9. Audits and Inspections 
As stipulated by 21 CFR §312.58 and ICH guidelines for GCP, a representative of 
the Sponsor, the FDA, or other regulatory agencies may conduct periodic site audits 
or inspections.  The Investigator or designee will provide these representatives with 
access to all requested materials, including eCRFs and supporting source 
documents.  In addition, the Investigator or other qualified study site personnel are to 
be available to answer questions, hold interviews, and provide facility tours, if 
requested. 
12.10. Data Collection and Handling 
The Investigator is responsible for complying with the requirements for all 
assessments and data collection (including patients not receiving protocol-required 
therapies), as stipulated in the protocol for each patient in the study.  For patients 
who withdraw prior to completion of all protocol-required visits and are unable or 
unwilling to continue the SOA (as described in Section 7.1), the Investigator may 


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search publicly available records (where permitted) to ascertain survival status.  
This ensures that the data set(s) produced as an outcome of the study is/are as 
comprehensive as possible. 
The Investigator agrees to maintain adequate case histories for the patients treated 
as part of the research under this protocol.  Data collection will involve the use of the 
electronic data capture (EDC) system, to which only authorized personnel will have 
access.  The Investigator agrees to maintain accurate eCRFs or paper CRFs and 
source documentation as part of the case histories.  The Sponsor will supply the 
eCRF, which will be completed in English. 
The Investigator or designee must enter all results collected during the clinical study 
into eCRFs.  Guidelines for completion of eCRFs will be reviewed with study site 
personnel at the site initiation visits.  Investigators are responsible for approval of the 
entered/corrected data.  Detailed instructions may be found in the other study 
specific documents. 
All entries made on the eCRF, must be verifiable against source documents.  
In addition to periodic monitoring occurring within the system by study monitors, 
programmatic edit checks and data listings will be used to review the data for 
completeness, logic, and adherence to study protocol.  As a result of this monitoring 
and these checks, queries may be electronically issued to the clinical study sites and 
electronically resolved by those sites. 
All data collected in the context of this study will be stored and evaluated according 
to regulatory requirements and applicable guidance for electronic records.  Also, 
data will be stored and evaluated in such a way as to assure patient confidentiality in 
accordance with the legal and regulatory requirements applying to protected health 
information.  Study records (e.g., copies of eCRFs, regulatory documents) will be 
retained at the study site, along with adequate source documentation.  The study file 
and all source data must be retained for the time period required by applicable 
regulatory requirements and will not be destroyed until written notification is given by 
the Sponsor or designee for destruction. 


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12.11. Maintenance of Source Documents and Record Retention 
As stipulated by 21 CFR §312.57 and ICH E6 GCP Consolidated Guidance 
Section 8, the Investigator or designee will maintain source documentation for this 
clinical study that documents the treatment and study course of patients as 
described in the study manual. 
Source documents are original documents, data, and records from which the 
patient’s eCRF data are obtained.  These include, but are not limited to hospital 
records, clinical and office charts, laboratory and pharmacy records, diaries, 
microfiches, radiographs, and correspondence. 
The Investigator and study staff are responsible for maintaining a comprehensive 
and centralized filing system of all study-related (essential) documentation, suitable 
for inspection at any time by representatives from the Sponsor and/or applicable 
regulatory authorities. 
The Investigator must retain all essential documents for this clinical study until at 
least 2 years after the last approval of a marketing application in an ICH region and 
until there are no pending or contemplated marketing applications in an ICH region, 
or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of Hu5F9-G4.  However, the Investigator may need to retain these 
documents for a longer period, if required by the applicable regulatory requirements 
or by an agreement with the Sponsor.  A Sponsor representative will be responsible 
for informing the Investigator and study site regarding when they no longer need to 
retain these documents.  Before destroying any records, the Investigator must notify 
the Sponsor and reach agreement on record destruction, or the Sponsor may 
request an additional retention period. 
 
 
 
. 
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12.13. Financing and Insurance 
The Sponsor maintains clinical trial insurance coverage for this study in accordance 
with the laws and regulations of the country in which the study is performed. 
12.14. Publication Policy 
The Forty Seven Inc. publication policy is detailed in the Publication Charter. 
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13. REFERENCES 
Blazar BR, Lindberg FP, Ingulli E, et al. CD47 (integrin-associated protein) 
engagement of dendritic cell and macrophage counterreceptors is required to 
prevent the clearance of donor lymphohematopoietic cells. J Exp Med 
2001;194(4):541-549. 
Bohnsack O, Ludajic K, and Hoos A. Adaptation of the immune-related response 
criteria: irRECIST. Annals of Oncology. 2014;25(4): iv361-iv372. 
Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody 
in patients with advanced cancer. N Engl J Med 2012;366(26):2455-65 
Chao MP, Alizadeh AA, Tang C, et al. Anti-CD47 antibody synergizes with rituximab 
to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell. 
2010a;142(5):699-713. 
Chao MP, Jaiswal S, Weissman-Tsukamoto R, et al. Calreticulin is the dominant 
pro-phagocytic signal on multiple human cancers and is counterbalanced by CD47. 
Sci Transl Med. 2010b;2(63):63ra94. 
Chao MP, Alizadeh AA, Tang C, et al. Therapeutic antibody targeting of CD47 
eliminates human acute lymphoblastic leukemia. Cancer Res. 
2011a;71(4):1374-1384. 
Chao MP, Tang C, Pachynski RK, et al. Extranodal dissemination of non-Hodgkin 
lymphoma requires CD47 and is inhibited by anti-CD47 antibody therapy. Blood. 
2011b;118(18):4890-4901. 
Chao MP, Majeti R, Weissman IL. Programmed cell removal: a new obstacle in the 
road to developing cancer. Nat Rev Cancer. 2012;12(1):58-67. 
Davis A, Tinker AV, Friedlander M. “Platinum resistant” ovarian cancer: What is it, 
who to treat and how to measure benefit? Gynecol Oncol 2014;133:624-631. 
Disis ML, Patel MR, Pant S, et al. Avelumab (MSB0010718C; anti-PD-L1) in patients 
with recurrent/refractory ovarian cancer from the JAVELIN Solid Tumor phase 1b 
trial: Safety and clinical activity. J Clin Oncol 34, 2016 (suppl; abstr 5533). 
Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, 
co-stimulates T cell proliferation and interleukin-10 secretion. Nat Med 
1999;5:1365-69. 
Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell 
apoptosis: a potential mechanism of immune evasion. Nat Med 2002; 8:793-800. 
[Erratum, Nat Med 2002; 8:1039.] 


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Edris B, Weiskopf K, Volkmer AK, et al. Antibody therapy targeting the CD47 protein 
is effective in a model of aggressive metastatic leiomyosarcoma. Proc Natl Acad Sci 
USA. 2012a;109(17):6656-6661. 
Edris B, Weiskopf K, Weissman IL, et al. Flipping the script on macrophages in 
leiomyosarcoma. Oncoimmunology 2012b;1(7):1202-1204. 
Eisenhauer E, Therasse P, Bogaerts J, et al. New response evaluation criteria in 
solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45(2): 
228-247. 
Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory 
receptor by a novel B7 family member leads to negative regulation of lymphocyte 
activation. J Exp Med 2000;192:1027-34. 
Freshwater T, Kondic A, Ahamadi M, et al. Evaluation of dosing strategy for 
pembrolizumab for oncology indications. J Immunother Cancer. 2017;5:43. 
Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab 
(Anti PD-1) in melanoma. N Engl J Med 2013;369:134-44. 
Herbst RS, Soria JC, Kowanetz M, et al. Predictive correlates of response to the 
anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515:563-567. 
Iwai Y, Ishida M, Tanaka Y, et al. Involvement of PD-L1 on tumor cells in the escape 
from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl 
Acad Sci USA 2002;99:12293-97. 
Jaiswal S, Jamieson CH, Pang WW, et al. CD47 is upregulated on circulating 
hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell. 
2009;138(2):271-285. 
Kim D, Wang J, Willingham SB, et al. Anti-CD47 antibodies promote phagocytosis 
and inhibit the growth of human myeloma cells. Leukemia. 2012;26(12):2538-2545. 
Latchman Y, Wood CR, Chernova T, et al. PD-L1 is a second ligand for PD-1 and 
inhibits T cell activation. Nat Immunol 2001;2(3):261-68. 
Liu X, Pu Y, Cron K, et al. CD47 blockade triggers T cell-mediated destruction of 
immunogenic tumors. Nat Med. 2015a;21(10):1209-1215. 
Liu J, Wang L, Zhao F, et al. Pre-clinical development of a humanized anti-CD47 
antibody with anti-cancer therapeutic potential. PLoS One. 2015b;10(9):e0137345. 
Majeti R, Chao MP, Alizadeh AA, et al. CD47 is an adverse prognostic factor and 
therapeutic antibody target on human acute myeloid leukemia stem cells. Cell. 
2009;138(2):286-299. 


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Okazawa H, Motegi S, Ohyama N, et al. Negative regulation of phagocytosis in 
macrophages by the CD47-SHPS-1 system. J Immunol 2005;174(4):2004-2011. 
Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649 655. 
Oldenborg PA, Zheleznyak A, Fang YF, et al. Role of CD47 as a marker of self on 
red blood cells. Science 2000;288(5473):2051-2054. 
Pollard JW. Tumour-educated macrophages promote tumour progression and 
metastasis. Nature Rev Cancer. 2004;4:71-78. 
Rustin GJ, Vergote I, Eisenhauer E, et al. Gynecological Cancer Intergroup. 
Definitions for response and progression in ovarian cancer clinical trials 
incorporating RECIST 1.1 and CA 125 agreed by the Gynecological Cancer 
Intergroup (GCIG). Int J Gynecol Cancer. 2011 Feb;21(2):419-23. 
Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1 (PD-L1) pathway to 
activate anti-tumor immunity. Curr Opin Immunol 2012a;24:207-12. 
Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of 
anti-PD-1 antibody in cancer. N Engl J Med 2012b;366(26):2443-54. 
Tseng D, Volkmer JP, Willingham SB, et al. Anti-CD47 antibody-mediated 
phagocytosis of cancer by macrophages primes an effective antitumor T-cell 
response. Proc Natl Acad Sci USA. 2013;110(27):11103-11108. 
Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by 
inhibiting adaptive immune resistance. Nature. 2014;515:568-571. 
Wang DD, Zhang S, Zhao H, et al. Fixed dosing versus body size-based dosing of 
monoclonal antibodies in adult clinical trials. J Clin Pharmacol 2009;49(9):1012-24. 
Willingham SB, Volkmer JP, Gentles AJ, et al. The CD47-signal regulatory protein 
alpha (SIRPα) interaction is a therapeutic target for human solid tumors. Proc Natl 
Acad Sci USA. 2012;109(17):6662-6667. 
Zhang M, Hutter G, Kahn S, et al. Anti-CD47 treatment stimulates phagocytosis of 
glioblastoma by M1 and M2 polarized macrophages and promotes M1 polarized 
macrophages in vivo. PLoS One. 2016;11(4):e0153550. 
Zhao X, Suryawanshi S, Hruska M, et al. Assessment of nivolumab benefit-risk 
profile of a 240-mg flat dose relative to a 3-mg/kg dosing regimen in patients with 
advanced tumors. Ann Oncol. 2017;28(8):2002-2008. 


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14. APPENDICES 
Appendix A.  Avelumab Study Information for JAVELIN 100 
 
JAVELIN 100 Study Title:  A Randomized, Open-label, Multicenter, Phase 3 Study 
To Evaluate The Efficacy And Safety Of Avelumab (msb0010718c) In Combination 
With And/or Following Chemotherapy In Patients With Previously Untreated 
Epithelial Ovarian Cancer Javelin Ovarian 100 
Available online: 
https://clinicaltrials.gov/ct2/show/NCT02718417?term=JAVELIN&cond=Ovarian+Ca
ncer&rank=1 
Accessed 6 April 2018 
Appendix B.  Avelumab Prescribing Information 
Avelumab (BAVENCIO®) Prescribing Information (3/2017 Version) 
Available online: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761049s000lbl.pdf 
Accessed 30 January 2018 
Appendix C.  National Cancer Institute Common Terminology Criteria for 
Adverse Events 
Common Terminology Criteria for Adverse Events (CTCAE) of the National Cancer 
Institute (NCI), Version 4.03 
Publication date: 28 May 2009 (v4.03: 14 June 2010) 
https://evs.nci.nih.gov/ftp1/CTCAE/ CTCAE_4.03/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf 
Accessed 23 July 2018 


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Appendix D.  Eastern Cooperative Oncology Group Performance Status 
Table 14-1. 
Eastern Cooperative Oncology Group Performance Status 
Grade 
Performance Status Criteria 
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 sedentary nature (light housework, office work). 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
 
Publication: 
Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655. 


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Appendix E.  Peripheral Smear Assessment 
Peripheral smears will be assessed by the designated hematopathology service 
using the following guidelines: 
RBC Agglutination 
0–9%  
Not reported/Absent 
10–19% 
1+ 
20–50% 
2+ 
51–75% 
3+ 
>75% 
4+ 
Spherocytes 
0–1 cells/100 RBCs 
Not reported/Absent 
2–5 cells/100 RBCs 
1+ 
>5–10 cells/100 RBCs 
2+ 
>10–30 cells/100 RBCs 
3+ 
>30 cells/100 RBCs 
4+ 
RBC Fragments/Schistocytes 
0 cells/100 RBCs 
Not reported/Absent 
1–2 cells/100 RBCs 
1+ 
>2–5 cells/100 RBCs 
2+ 
>5–10 cells/100 RBCs 
3+ 
>10 cells/100 RBCs 
4+ 
Abbreviations:  RBCs = red blood cells. 
Note:  These guidelines are adapted from the Stanford Health Care Peripheral Blood Slide Review 
Manual, Version 3.0, 2015. 
 
All other observed findings:  Report according to local laboratory 
hematopathology standard procedures. 
If sites are not able to quantify the degree of peripheral smear findings noted above, 
then the presence or absence of RBC agglutination, spherocytes, and/or RBC 
fragments/schistocytes must be reported at a minimum. 

SAP_001.pdf: 
5F9006 
Statistical Analysis Plan, Version 1.0 
Page 1 
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STATISTICAL ANALYSIS PLAN 
TITLE: 
A PHASE 1B TRIAL OF HU5F9-G4 IN COMBINATION WITH 
AVELUMAB IN SOLID TUMOR PATIENTS AND CHECKPOINT 
INHIBITOR NAÏVE OVARIAN CANCER PATIENTS WHO 
PROGRESS WITHIN 6 MONTHS OF PRIOR PLATINUM 
CHEMOTHERAPY 
 
PROTOCOL NUMBER: 
5F9006 
STUDY DRUG: 
Magrolimab (Hu5F9-G4) 
VERSION NUMBER: 
1.0 
SPONSOR: 
Forty Seven Inc 
PLAN PREPARED BY: 
 
DATE: 
22 July, 2020 
 
Confidentiality Statement 
The concepts and information contained herein are confidential and proprietary and shall not be 
disclosed in whole or part without the express written consent of Forty Seven Inc. 
PPD
• Forty Seven 


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NUMBER: 
FortySeven 
STATISTICAL ANALYSIS PLAN 
A PHASE 1B TRIAL OF HUSF9-G4 IN COMBINATION WITH 
AVELUMAB IN SOLID TUMOR PATIENTS AND CHECKPOINT 
INHIBITOR NMVE OVARIAN CANCER PATIENTS WHO 
PROGRESS WITHIN 6 MONTHS OF PRIOR PLATINUM 
CHEMOTHERAPY 
5F9006 
STUDY DRUG: 
Magrolimab (Hu5F9-G4) 
VERSION NUMBER: 1.0 
SPONSOR: 
Forty Seven Inc 
PLAN 
PREPAREDPPD 
BY: 
c..a..;;.... ____ 
__,, 
DATE: 
22 July, 2020 
Confidentiality Statement 
The concepts an.d information contained herein are confidential and proprietary and shall not be 
disclosed in whole or part without the express written consent of Forty Seven Inc. 
APPROVAL 
Upon review of this document, including table, listing, and figure shells, the undersigned 
approves the Statistical Analysis Plan. The analysis methods and data presentation are 
acceptable. 
Signature 
Date 
PPD 
7f-;).l~?c 
J>PD 
J 
J 
Forty Seven Inc. 
PPD 
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IPPD 
J 
I 
Forty Seven Inc. 


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TABLE OF CONTENTS 
APPROVAL .................................................................................................................................. 2 
TABLE OF CONTENTS ............................................................................................................... 3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................ 5 
1 
INTRODUCTION ............................................................................................................. 6 
1.1 
Study Design ................................................................................................................... 6 
1.1.1 
Part 1 Safety Run-In Cohort ........................................................................................ 6 
1.1.2 
Part 2 Expansion Cohort .............................................................................................. 7 
1.2 
Study Objectives and Endpoints ..................................................................................... 7 
1.3 
Sample Size Determination............................................................................................. 9 
2 
ANALYSIS SETS ............................................................................................................. 9 
3 
PATIENT INFORMATION .............................................................................................. 9 
3.1 
Patient Disposition ........................................................................................................ 10 
3.2 
Protocol Deviations ....................................................................................................... 10 
3.3 
Demographics and Baseline Characteristics ................................................................. 10 
3.4 
Medical History ............................................................................................................ 10 
3.5 
Prior Cancer Treatments ............................................................................................... 10 
3.6 
Prior and Concomitant Medications ............................................................................. 10 
3.7 
Extent of Exposure ........................................................................................................ 11 
4 
EFFICACY ANALYSIS ................................................................................................. 11 
5 
PHARMACOKINETIC ANALYSES ............................................................................. 12 
5.1 
Pharmacokinetic Analysis ............................................................................................. 12 
5.2 
Immunogenicity Analysis ............................................................................................. 12 
6 
SAFETY ANALYSIS ...................................................................................................... 12 
6.1 
Adverse Events ............................................................................................................. 12 
6.2 
Deaths ........................................................................................................................... 13 
6.3 
Clinical Laboratory Evaluation ..................................................................................... 13 
6.4 
Vital Signs ..................................................................................................................... 14 


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6.5 
Physical Examination.................................................................................................... 14 
6.6 
Electrocardiogram ......................................................................................................... 14 
6.7 
Peripheral Blood Smear ................................................................................................ 14 
7 
CHANGES TO PROTOCOL-SPECIFIED ANALYSES ............................................... 14 
8 
REFERENCES ................................................................................................................ 15 
  


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ATC 
anatomical\therapeutic\chemical 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTSC 
Clinical Trial Steering Committee 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
eCRF 
electronic case report form 
GCIG 
Gynecologic Cancer InterGroup 
irRECIST 
Guidelines for the Evaluation of Immune Therapy Activity in Solid Tumors:  Immune-
related Response Criteria  
ORR 
objective response rate 
OS 
overall survival 
PFS 
progression-free survival  
PK 
pharmacokinetics 
PT 
preferred term 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TRAE 
treatment-related adverse event 
TTP 
time to progression 
WHO 
World Health Organization 
 


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1 
INTRODUCTION 
This document outlines the statistical methods and variable definitions to be implemented during 
the analyses of data in evaluation of efficacy, safety, pharmacokinetics (PK) and immunogenicity 
of the clinical trial described in the Forty Seven Inc. protocol for Study 5F9006 entitled “A Phase 
1b Trial of Hu5F9 G4 in Combination with Avelumab in Solid Tumor Patients and Checkpoint 
Inhibitor Naïve Ovarian Cancer Patients Who Progress within 6 Months of Prior Platinum 
Chemotherapy” Amendment 3, dated 22 December 2018. Analyses of biomarker data are out of 
scope of this SAP and will be described in a separate document. 
Analysis methods specified in this document take precedence over those described in the 
protocol should there be any difference. 
1.1 
Study Design 
This is an open label, multicenter, Phase 1b trial investigating the combination of magrolimab 
and avelumab in patients with solid tumors and checkpoint inhibitor-naïve ovarian cancer who 
progressed within 1-6 months of receiving platinum containing chemotherapy. Checkpoint-
inhibitor-naïve patients are defined as those who have not been previously treated with an anti-
PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody (including ipilimumab, 
tremelimumab, or any other antibody or drug specifically targeting T-cell co-regulatory 
proteins). 
The study will be conducted in 2 parts: 
• Part 1: safety run-in cohort 
• Part 2: expansion cohort 
1.1.1 
Part 1 Safety Run-In Cohort 
In Part 1 of the study, patients with solid tumors will be treated with magrolimab + avelumab to 
examine the safety and PK of this study treatment.  A safety run-in cohort will treat 6 patients 
evaluable for dose limiting toxicity (DLT).  
The dose levels and schedules for both study drugs are described in protocol synopsis Table 2. 
Specifically, in the first dose level cohort, patients will be treated with a priming dose of 
magrolimab at 1 mg/kg on Day 1, followed by 4 weekly doses at 30 mg/kg on Days 8, 15, 22, and 
29 in a 35-day long Cycle 1. In the second dose level cohort, patients will be treated with a priming 
dose of magrolimab at 1 mg/kg on Day 1, followed by 5 doses at 45 mg/kg on Days 8, 11, 15, 22, 
and 29 in a 35-day long Cycle 1. 
In both dose level cohorts, on Days 8 and 22, 800 mg avelumab will be administered. On any day 
when both drugs are administered, magrolimab infusion will begin at least 1 hour after completion 


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of the avelumab infusion. Starting in Cycle 2, the cycle length will be 28 days, and magrolimab 
will be administered at 30 mg/kg in the first dose level cohort or 45 mg/kg in the second dose level 
cohort, in combination of 800 mg avelumab, every 2 weeks on Days 1 and 15 in each cycle. 
DLT will be monitored from administration of the priming dose on Day 1 to the end of Cycle 1 
(Day 35).  The first patient in each dose level cohort will be treated for 14 days prior to enrolling 
additional patients. If no more than one DLT event occurs after the 6 patients evaluable for DLT 
assessment have safely completed the DLT assessment period in a safety run-in cohort, the dose 
level will be deemed to be safe by the Clinical Trial Steering Committee (CTSC). The 
recommended dose and schedule must have a DLT rate less than 33%. The decision will be made 
by the CTSC after all available clinical, 
 and PK data are reviewed. 
 
 
1.1.2 
Part 2 Expansion Cohort 
In Part 2 of the study, patients with checkpoint-inhibitor-naïve ovarian cancer, fallopian tube 
cancer and primary peritoneal carcinoma who have previously progressed within 1 – 6 months of 
receiving platinum chemotherapy will be treated with the recommended dose and schedule 
determined by CTSC in the expansion cohort, in order to confirm safety, PK, 
 
and to document preliminary efficacy in this population. Study treatment may be continued until 
an unacceptable drug related toxicity occurs or until disease progression according to irRECIST. 
Pre-treatment and on-treatment biopsy sample collection is mandatory, unless medically not 
feasible determined by the Investigator and Sponsor (refer to protocol section 7.3.11).  
1.2 
Study Objectives and Endpoints 
PRIMARY 
OBJECTIVES 
ENDPOINTS 
• 
To investigate the safety and tolerability of 
magrolimab + avelumab in the safety run-in 
cohorts of patients with advanced solid 
tumor  
• 
To confirm the safety and tolerability and to 
evaluate the anti-tumor activity of 
magrolimab + avelumab, based on RECIST 
v1.1 (Eisenhauer 2009), in patients with 
checkpoint-inhibitor-naïve ovarian cancer, 
fallopian tube cancer and primary peritoneal 
carcinoma who have previously progressed 
• 
DLT events and adverse events (AEs) 
graded according to National Cancer 
Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) v 4.03 or 
customized AE severity grading for 
hemagglutination and microangiopathy, as 
defined in protocol Section 6.5.1.3.  
• 
Objective response rate (ORR) as defined 
by the investigator according to RECIST 
v1.1. 
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within 1 – 6 months of receiving platinum 
chemotherapy  
SECONDARY 
OBJECTIVES 
ENDPOINTS 
• 
To determine a recommended dose of 
magrolimab + avelumab in patients with 
advanced solid tumor 
• 
To examine the PK profile of magrolimab in 
combination with avelumab 
• 
To examine the immunogenicity of 
magrolimab in combination with avelumab 
• 
To evaluate the anti-tumor activity of 
magrolimab + avelumab based on irRECIST 
(Bohnsack 2014) and, where applicable, the 
Gynecologic Cancer Intergroup (GCIG) 
response criteria (Rustin 2011), in patients 
with checkpoint-inhibitor-naïve ovarian 
cancer, fallopian tube cancer and primary 
peritoneal carcinoma who have previously 
progressed within 1 – 6 months of receiving 
platinum chemotherapy 
• 
To assess additional efficacy endpoints 
including duration of response (DOR), time 
to tumor progression (TTP), progression-free 
survival (PFS), and overall survival (OS) in 
patients with checkpoint-inhibitor-naïve 
ovarian cancer, fallopian tube cancer and 
primary peritoneal carcinoma who have 
previously progressed within 1 – 6 months of 
receiving platinum chemotherapy 
• 
To evaluate the impact of magrolimab in 
combination with avelumab on the myeloid 
cell populations in the tumor 
microenvironment, as assessed in sequential 
tumor biopsies, in patients with platinum 
resistant ovarian cancer 
• 
Recommended dose and schedule of 
magrolimab + avelumab 
• 
Serum concentrations of magrolimab 
collected at selected time points 
• 
Anti-drug antibodies to magrolimab 
• 
ORR as defined by the investigator 
according to irRECIST and GCIG response 
criteria. 
• 
DOR, TTP, PFS, and OS 
• 
Immunohistochemical staining of myeloid 
cells in formalin-fixed, paraffin-embedded 
tissues 


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1.3 
Sample Size Determination 
This trial will include a total of up to 40 patients.  This sample size includes both Parts 1 and 2 of 
the study, allowing for patient replacement if not evaluable for DLT assessment in Part 1.  In Part 
1, it is assumed that no more than 2 DLT events in each cohort of 6 DLT evaluable patients would 
occur. In Part 2, it is planned to enroll a single expansion cohort of 20 patients with checkpoint-
inhibitor-naïve ovarian cancer, fallopian tube cancer and primary peritoneal carcinoma who have 
previously progressed within 1 – 6 months of receiving platinum chemotherapy.  No formal 
hypothesis testing will be done. This sample size will provide about 45% power to have the lower 
bound of the 80% confidence interval of ORR to exclude 10% if the ORR is 30% or higher.   
2 
ANALYSIS SETS 
• DLT Evaluable Analysis Set:  includes patients in Part 1 who either experienced any DLT 
event any time after initiation of the first infusion of magrolimab or any infusion of 
avelumab and during the 5-week DLT assessment period, or who received at least 4 (or 5 
if assigned to the second dose level 45 mg/kg) complete infusions of magrolimab at the 
maintenance level and 2 complete infusions of avelumab.  Patients who are not evaluable 
for dose review decisions will be replaced in the cohort. 
• All Treated Patients:  includes all patients who received at least 1 dose of any study drugs. 
Summary tables of disposition, demographics and other baseline characteristics, and safety 
data will be performed on the All Treated Patients. 
• Efficacy Analysis Set:  includes checkpoint inhibitor-naïve patients with ovarian cancer, 
fallopian tube cancer and primary peritoneal carcinoma, who have previously progressed 
within 6 months of receiving platinum chemotherapy and received at least one dose of 
magrolimab during this study. Primary efficacy analysis will be performed on the Efficacy 
Analysis Set. 
• PK Analysis Set:  includes patients who received any amount of magrolimab with at least 
one detectable post-treatment serum concentration of magrolimab are evaluable for PK 
analysis. 
• Immunogenicity Analysis Set: includes patients with at least one reported ADA result 
will be included in the immunogenicity analysis set. 
3 
PATIENT INFORMATION 
Disposition, demographics and other baseline characteristics, medical history, disease history, 
prior anticancer treatment, prior and concomitant medications, premedication, and extent of 
exposure to the study treatment will be presented for All Treated Patients. 


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3.1 
Patient Disposition 
The disposition table will include the following summaries:  the number of patients treated, the 
number of patients who discontinued from the study treatment and of those from the study, reasons 
for discontinuation, duration of treatment (months), and duration of follow up (months).  The 
summaries will be provided for each dosing cohort (Part 1) or the expansion cohort (Part 2), or at 
each maintenance dosing level. 
3.2 
Protocol Deviations 
Patients with important protocol deviations will be identified and documented by the clinical team. 
3.3 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics including age, sex, ethnicity, race, weight as well as 
disease characteristics will be summarized. 
3.4 
Medical History  
A listing will be provided for medical history. 
3.5 
Prior Cancer Treatments 
The number and percentage of patients with each type of prior anticancer treatment (prior 
radiotherapy, prior cancer-related surgery, and prior cancer-related systemic therapy) will be 
summarized.  The number of prior lines of cancer-related systemic therapies will also be 
summarized. 
3.6 
Prior and Concomitant Medications 
Concomitant medication verbatim terms on electronic case report forms (eCRFs) will be coded to 
Anatomical/Therapeutic/Chemical (ATC) class and Preferred Names using the World Health 
Organization (WHO) Drug Dictionary Enhanced (version March 1, 2014). 
Concomitant medications will be summarized by WHO ATC class and preferred name.  The 
summarization includes all the concomitant medications taken any time while on study treatment 
(ie, from the date of first dose through the date of last dose of the study treatment), with exception 
of the premedication described in Section 6.1.2 of the protocol, which will be summarized 
separately (see the next subsection).  Each patient will be counted once for each preferred name, 
and each ATC class. 
Prior medication is defined as any medication with a start date prior to the date of first dose, 
regardless of when the stop date is.  A listing of prior medication together with concomitant 
medications will be provided.  


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Premedication is required before administration of the first 2 infusions of magrolimab (inclusive 
of the priming dose) and before the first 4 infusions of avelumab.  The number and percentage of 
patients who received the following premedication will be summarized:  
• Oral acetaminophen 650 to 1000 mg and oral or intravenous diphenhydramine 25 mg, or 
comparable regimen on the date of but prior to the first 2 infusions of magrolimab 
(inclusive of the priming dose)  
• An antihistamine and acetaminophen (for example, 25 to 50 mg intravenous or oral 
diphenhydramine and 500 to 650 mg oral acetaminophen) approximately 30 to 60 minutes 
prior to the first 4 infusions of avelumab  
3.7 
Extent of Exposure 
Exposure to study treatment will be summarized in each cohort.  Descriptive statistics will be 
provided for the following data for each study drugs (magrolimab, avelumab): treatment duration; 
total number of study drug infusions; cumulative dose administered; the number of missed/delayed 
doses, including those due to AE; the number of dose reductions; the number of dose interruptions, 
including those due to AE; and median time to first missed, delayed, or interrupted dose due to AE 
or dose reduction.  
4 
EFFICACY ANALYSIS 
Confirmed best response based on RECIST v1.1 and best response based on GCIG criteria will be 
summarized. The primary analysis will be based on the Efficacy Analysis Set, in which the ovarian 
cancer patients had documented progression within 6 months of receiving platinum chemotherapy 
and did not have any data that showed prior anticancer therapy of checkpoint inhibitor. A 
sensitivity analysis will be based on all ovarian cancer patients. ORR, defined as the proportion of 
patients who achieve a complete or partial response, will be calculated based on patients with 
measurable disease at baseline, with 95% confidence interval provided.  
DOR will be calculated for patients with confirmed response as time from the initial response until 
disease progression. 
PFS is defined as the duration of time from dose initiation to the first date of objectively 
documented disease progression per RECIST v1.1 or death, whichever occurred at first.  Patients 
who do not have documented disease progression and did not die will be censored at their last 
tumor assessment date.  OS is defined as the duration of time from dose initiation to the date of 
death due to any cause.  Patients who did not die will be censored at their last known alive date.  
Both PFS and OS will be summarized using Kaplan-Meier methods and summary statistics will 
include their 95% confidence intervals. 


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Efficacy data for patients who had solid tumors other than ovarian cancer will be reported in 
listings.   
5 
PHARMACOKINETIC ANALYSES 
5.1 
Pharmacokinetic Analysis 
The PK Analysis Set will be used in the analysis of PK data. Descriptive statistics of magrolimab 
concentration data will be provided. Individual and mean serum concentration-time profiles of 
magrolimab per cohort for each study part will be generated. Non-compartmental PK data analysis 
may be performed when data allows and PK parameters such as Cmax and AUC will be reported 
when appropriate. Additional parameters may be calculated as deemed appropriate.  
5.2 
Immunogenicity Analysis 
The prevalence, incidence and titer of anti-magrolimab antibodies (antidrug antibodies or ADA) 
will be evaluated for individual patients and will be listed and summarized for each dose cohort 
for each study part and for the pooled patient population.  ADA incidence, prevalence, and 
transience versus persistence will be summarized.  
 
 
 
  
6 
SAFETY ANALYSIS 
All safety analyses will be performed by the actual magrolimab maintenance dose level based on 
the Safety Analysis Set. 
6.1 
Adverse Events 
Treatment-emergent adverse events (TEAE) will be summarized in each cohort.  TEAEs are 
defined as those AEs that worsened or occurred during or after a patient’s first dose of any study 
drug and those existing AEs that worsened during the study and within 30 days after the last 
administration of any study drug or initiation of new anticancer therapy, whichever occurred first.  
If it cannot be determined whether the AE is treatment-emergent due to a partial onset date then 
the AE will be included in the TEAE summary.  Verbatim terms on eCRFs will be coded to system 
organ class (SOCs) and preferred terms (PTs) using the Medical Dictionary for Regulatory 
Activities Version 19.0.  NCI-CTCAE Version 4.03 will be used to summarize type and severity 
of the events, except for hemagglutination and microangiopathy events, which will be assessed per 
the protocol specified (Section 6.5.1.3) severity scoring.  
The following summaries will be performed: 
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• Overview of AEs.     
• Patient incidence of TEAEs by PT. 
• Patient incidence of treatment-related adverse events (TRAEs) by PT. 
• Patient incidence of TEAEs by SOC and PT, showing each grade and overall. 
• Patient incidence of serious TEAEs by SOC and PT, showing each grade and overall. 
• Patient incidence of TRAEs by SOC and PT. 
• Patient incidence of Grade 3 or higher TEAEs by SOC and PT. 
• Patient incidence of Grade 3 or higher TRAEs by SOC and PT. 
• Patient incidence of TEAEs as part of an infusion reaction identified by the investigator by 
SOC and PT, showing each grade and overall. 
• Patient incidence of TEAEs leading to study drug discontinuation by SOC, PT, and worst 
grade. 
• Patient incidence of TEAEs leading to dose interruption by SOC and PT. 
• Patient incidence of TEAEs leading to dose delay/reduction by SOC and PT. 
A further summary of the number of patients experiencing DLT events and the average number of 
infusions in these patients will be tabulated.  
Listings of all AEs including TEAEs, TEAEs related to either magrolimab or avelumab, Grade 3 
or higher TEAEs, TEAEs that the investigator identified as part of an infusion reaction, serious 
TEAEs, TEAEs leading to study discontinuation, TEAEs leading to interruption or dose 
delay/reduction, DLT events, and deaths will be provided.  
6.2 
Deaths 
All deaths and causes of death on study will be summarized and listed.  
6.3 
Clinical Laboratory Evaluation   
Selected laboratory parameters (serum chemistry, hematology, prothrombin time / international 
normalized ratio, and activated partial thromboplastin time) will be summarized. 
Laboratory parameters will be graded according to CTCAE Version 4.03.  The worst postbaseline 
CTCAE grade will be summarized using a shift table to assess changes from baseline for the key 
variables.  Summaries of treatment-emergent laboratory toxicities of serum chemistry and 
hematology will be tabulated by counts and percentages.  
Laboratory data listings will include CTCAE grades and flags for those values outside the 
reference ranges.  Urinalysis examination will only be presented in a data listing.  


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6.4 
Vital Signs 
Vital sign measurement results will only be provided in a data listing.  
6.5 
Physical Examination 
Physical examination results will only be provided in a data listing.  
6.6 
Electrocardiogram 
Electrocardiogram results will only be provided in a data listing.  
6.7 
Peripheral Blood Smear 
Peripheral blood smear parameters will be summarized using frequency counts with percentages 
at each time point.  
7 
CHANGES TO PROTOCOL-SPECIFIED ANALYSES 
The following modifications have been made to the analyses specified in Protocol Amendment 3: 
• The definition of treatment-emergent period is updated to specify an end date for each 
patient’s reporting period to be within 30 days after the last administration of study drug 
or initiation of new anticancer therapy, whichever occurred first.  
• The Dose Evaluation Set is renamed as the DLT Evaluable Analysis Set for the same 
purpose of DLT assessment. Patients who experienced any DLT event are evaluable for 
DLT as long as the patient received any infusion of magrolimab, regardless of dose level, 
or any infusion of avelumab.  Patients who didn’t experience any DLT event are evaluable 
only if they completed the scheduled study treatment that was assigned, based on the 
protocol synopsis Table 2. During the 5-week DLT assessment period, in addition to 2 
infusions of avelumab, patients assigned to dose cohort 1 receive 4 magrolimab infusions 
at 30 mg/kg and patients assigned to dose cohort 2 receive 5 magrolimab infusions at 45 
mg/kg. 
• The definition of Efficacy Analysis Set is modified to support the summary of efficacy 
data.  First, included in the summary are   checkpoint inhibitor-naïve patients with ovarian 
cancer, fallopian tube cancer and primary peritoneal carcinoma who have previously 
progressed within 6 months of receiving platinum chemotherapy, according to the target 
patient population for the expansion cohort in the Part 2 for efficacy evaluation.  Second, 
patients who received at least one dose of magrolimab are included to support the primary 
analysis of PFS and OS, as well as BOR.    
• Endpoint TTP will not be summarized.  
• The tumor assessment based on irRECIST will not be reported.  


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REFERENCES 
Bohnsack O, Ludajic K, and Hoos A. Adaptation of the immune-related response criteria: 
irRECIST. Annals of Oncology. 2014;25(4): iv361-iv372. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-247.  
Rustin GJ, Vergote I, Eisenhauer E, et al. Gynecological Cancer Intergroup. Definitions for 
response and progression in ovarian cancer clinical trials incorporating RECIST 1.1 and CA 125 
agreed by the Gynecological Cancer Intergroup (GCIG). Int J Gynecol Cancer. 2011 
Feb;21(2):419-23.