Clinical trial NCT02953782
Conditions: Solid Tumor Colorectal Cancer
Sponsor: Gilead Sciences
Start date: 2016-11-02; Completion date: 2020-02-10
Enrollment: 78 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The primary objectives of this study are: (Phase 1b) to investigate the safety and tolerability and to determine the recommended Phase 2 dose (RP2D) for magrolimab in combination with cetuximab; and (Phase 2) to evaluate overall response rate (ORR) of magrolimab in combination with cetuximab in participants with Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) mutant and KRAS wild-type colorectal cancer (CRC).

Detailed description:

Arms: arm 1: Participants with solid tumor will receive a priming dose of magrolimab 1 mg/kg of body weight by intravenous (IV) infusion (approximately 3 hours infusion) on Day 1 followed by a maintenance dose of magrolimab 10 mg/kg of body weight by IV infusion (approximately 2 hours infusion) weekly starting on Day 8 followed by Days 15 and 22 in combination with cetuximab at a loading dose of 300 mg/m\^2 infused over 120-minutes on Day 8 followed by a weekly maintenance dose of 200 mg/m\^2 infusions given over 60 minutes on Days 15 and 22, in Cycle 1. After Cycle 1 and thereafter, weekly maintenance dose for both magrolimab and cetuximab, will start on Day 1. Each cycle will consist of 4 weeks (28 days). Cetuximab will be administered 1 hour prior to magrolimab infusion on days when both are given. Treatment will be administered until unacceptable toxicity, voluntary withdrawal, or documented progressive disease (PD). arm 2: Participants with solid tumor will receive a priming dose of magrolimab 1 mg/kg of body weight by IV infusion (approximately 3 hours infusion) on Day 1 followed by a maintenance dose of magrolimab 10 mg/kg of body weight by IV infusion (approximately 2 hours infusion) weekly starting on Day 8 followed by Days 15 and 22 in combination with cetuximab at a loading dose of 400 mg/m\^2 infused over 120-minutes on Day 8 followed by a weekly maintenance dose of 250 mg/m\^2 infusions given over 60 minutes on Days 15 and 22, in Cycle 1. After Cycle 1 and thereafter, weekly maintenance dose for both magrolimab and cetuximab, will start on Day 1. Each cycle will consist of 4 weeks (28 days). Cetuximab will be administered 1 hour prior to magrolimab infusion on days when both are given. Treatment will be administered until unacceptable toxicity, voluntary withdrawal, or documented PD. arm 3: Participants with solid tumor will receive a priming dose of magrolimab 1 mg/kg of body weight by IV infusion (approximately 3 hours infusion) on Day 1 followed by a maintenance dose of magrolimab 20 mg/kg of body weight by IV infusion (approximately 2 hours infusion) weekly starting on Day 8 followed by Days 15 and 22 in combination with cetuximab at a loading dose of 400 mg/m\^2 infused over 120-minutes on Day 8 followed by a weekly maintenance dose of 250 mg/m\^2 infusions given over 60 minutes on Days 15 and 22, in Cycle 1. After Cycle 1 and thereafter, weekly maintenance dose for both magrolimab and cetuximab, will start on Day 1. Each cycle will consist of 4 weeks (28 days). Cetuximab will be administered 1 hour prior to magrolimab infusion on days when both are given. Treatment will be administered until unacceptable toxicity, voluntary withdrawal, or documented PD. arm 4: Participants with solid tumor will receive a priming dose of magrolimab 1 mg/kg of body weight by IV infusion (approximately 3 hours infusion) on Day 1 followed by a maintenance dose of magrolimab 30 mg/kg of body weight by IV infusion (approximately 2 hours infusion) weekly starting on Day 8 followed by Days 15 and 22 in combination with cetuximab at a loading dose of 400 mg/m\^2 infused over 120-minutes on Day 8 followed by a weekly maintenance dose of 250 mg/m\^2 infusions given over 60 minutes on Days 15 and 22, in Cycle 1. After Cycle 1 and thereafter, weekly maintenance dose for both magrolimab and cetuximab, will start on Day 1. Each cycle will consist of 4 weeks (28 days). Cetuximab will be administered 1 hour prior to magrolimab infusion on days when both were given. Treatment will be administered until unacceptable toxicity, voluntary withdrawal, or documented PD. arm 5: Participants with solid tumor will receive a priming dose of magrolimab 1 mg/kg of body weight by IV infusion (approximately 3 hours infusion) on Day 1 followed by a maintenance dose of magrolimab 45 mg/kg of body weight by IV infusion (approximately 2 hours infusion) weekly starting on Day 8 followed by Days 15 and 22 in combination with cetuximab at a loading dose of 400 mg/m\^2 infused over 120-minutes on Day 8 followed by a weekly maintenance dose of 250 mg/m\^2 infusions given over 60 minutes on Days 15 and 22, in Cycle 1. Participants will also receive a loading dose of magrolimab 45 mg/kg on Day 11 of Cycle 1. After Cycle 1, maintenance dose for both magrolimab and cetuximab will start on Day 1 with weekly dose in Cycle 2 and bi-weekly dose in Cycle 3 onwards for magrolimab. Each cycle will consist of 4 weeks. Treatment will be administered until unacceptable toxicity, voluntary withdrawal, or documented PD. arm 6: Participants with advanced colorectal cancer (CRC) who are KRAS wild type (KRASwt) and are refractory to anti-EGFRmAb therapy will receive a priming dose of magrolimab 1 mg/kg of body weight by IV infusion (approximately 3 hours) on Day 1 followed by a maintenance dose of magrolimab 30 mg/kg of body weight by IV infusion (approximately 2 hours) weekly starting on Day 8 followed by Days 15 and 22 in combination with cetuximab at a loading dose of 400 mg/m\^2 infused over 120-minutes on Day 8 followed by a weekly maintenance dose of 250 mg/m\^2 infusions given over 60 minutes on Days 15 and 22, in Cycle 1. After Cycle 1, maintenance dose for both magrolimab and cetuximab will start on Day 1; Days 8 and 22 are removed from Cycle 2 onwards for magrolimab. Each cycle will consist of 4 weeks. Cetuximab will be administered 1 hour prior to magrolimab infusion on days when both are given. Treatment will be administered until unacceptable toxicity, voluntary withdrawal, or documented PD. arm 7: Participants with advanced CRC with KRAS mutation (KRASm) who have progressed or are not candidates for oxaliplatin or irinotecan-based therapy will receive a priming dose of magrolimab 1 mg/kg of body weight by IV infusion (approximately 3 hours infusion) on Day 1 followed by a maintenance dose of magrolimab 30 mg/kg of body weight by IV infusion (approximately 2 hours infusion) weekly starting on Day 8 followed by Days 15 and 22 in combination with cetuximab at a loading dose of 400 mg/m\^2 infused over 120-minutes on Day 8 followed by a weekly maintenance dose of 250 mg/m\^2 infusions given over 60 minutes on Days 15 and 22, in Cycle 1. After Cycle 1, maintenance dose for both magrolimab and cetuximab will start on Day 1; Days 8 and 22 are removed from Cycle 2 onwards for magrolimab. Each cycle will consist of 4 weeks. Treatment will be administered until unacceptable toxicity, voluntary withdrawal, or documented PD. arm 8: Participants with advanced CRC with KRASm who have progressed or are not candidates for oxaliplatin or irinotecan-based therapy will receive a priming dose of magrolimab 1 mg/kg of body weight by IV infusion (approx. 3 hours) on Day 1 followed by a maintenance dose of magrolimab 45 mg/kg of body weight by IV infusion (approx. 2 hours) weekly starting on Day 8 followed by Days 15 and 22 in combination with cetuximab at a loading dose of 400 mg/m\^2 infused over 120-minutes on Day 8 followed by a weekly maintenance dose of 250 mg/m\^2 infusions given over 60 minutes on Days 15 and 22, in Cycle 1. Participants will also receive a loading dose of magrolimab 45 mg/kg of body weight on Day 11 of Cycle 1. After Cycle 1, maintenance dose for both magrolimab and cetuximab will start on Day 1; Days 8 and 22 are removed from Cycle 3 onwards for magrolimab. Each cycle will consist of 4 weeks. Treatment will be administered until unacceptable toxicity, voluntary withdrawal, or documented PD.
Interventions: intervention 1: Magrolimab intervention 2: Cetuximab
Intervention descriptions: intervention 1: Administered intravenously intervention 2: Administered intravenously

Protocol documents:
Prot_000.pdf: 
Hu5F9-G4 
Protocol 5F9004, Amendment 3 
Page 1 of 161 
CLINICAL STUDY PROTOCOL 
Protocol Title: 
A Phase 1b/2 Trial of Hu5F9-G4 in Combination with 
Cetuximab in Patients with Solid Tumors and Advanced 
Colorectal Cancer 
Protocol Number: 
5F9004 
lnvestigational Medicinal 
Product: 
Hu5F9-G4 in combination with cetuximab 
Indication: 
Solid tumors and colorectal cancer 
Development Phase: 
1b/2 
US IND Number: 
117687 
Sponsor: 
Medical Monitor: 
Study Monitor: 
Lead Investigator: 
Amendment 3 Date: 
Amendment 2 Date: 
Amendment 1 Date: 
Original Protocol Date: 
Telephon~ IP.PlJ 
Fax: PPD 
PPD 
PPD 
T eleph'_o_n_e_: lP .P lJ 
email: PPD 
PPD 
PPD 
Teleph'_o_n_e_,: lP .PD 
email: PPD 
---------
PD 
PD 
.PlJ 
~ elephone: [PPD 
------
28 September 2018 
29 January 2017 
1 September 2016 
29 July 2016 
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. 
Forty Seven Inc. 
Confidential 


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Compliance Statement: 
This study will be conducted in accordance with Protocol 5F9004, 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: 
PPD 
Date 
PD 
Forty Seven Inc. 
Forty Seven Inc. 
Confidential 


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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 reasons for amending the 5F9004 protocol are to modify the dose and 
schedule for Phase 1 cohorts, define the dose and schedule to be used in Phase 2, 
modify re-priming instructions, remove sample collection for receptor occupancy, 
allow for continuation of either drug in the combination as single-agent treatment, 
add assessment by iRECIST criteria, and to ensure consistency with other clinical 
studies of Hu5F9-G4 sponsored by Forty Seven Inc.   
The following is a list of substantial changes that have been made to the protocol: 
• Changed the Medical Monitor from 
 to 
 (Title page, Section 9.4). 
• Changed the Study Monitor from 
 to 
 
(Title page). 
• Added the following terms and abbreviations definitions list: disease control 
rate, Enrolled Analysis Set, Per-Protocol Analysis Set, every 2 weeks, 
Response Evaluation Criteria in Solid Tumors, and Safety Analysis Set 
(Abbreviations and Definitions). 
• Updated Hu5F9-G4 clinical safety data and clinical pharmacology data 
(Sections 1.2.4.1, 1.2.4.2, 1.5.1, and 6.1.5.2.1). 
• Modified the planned Phase 1b doses administered in Cohort 4, which 
included the removal of the Hu5F9-G4 loading dose on Cycle 1 Day 11 and 
specification that the Hu5F9-G4 maintenance is 30 mg/kg or 45 mg/kg. Added 
that up to 5 dose cohorts are anticipated. (Synopsis, Study Design Schema, 
Sections 1.5.1, 3, and 6.1, 11.2, and Table 1 and Table 4). 
• The Recommended Phase 2 dose and schedule (RP2DS) for Hu5F9-G4 was 
added. In Phase 2, patients will receive a priming dose of 1 mg/kg (i.e., no 
loading dose will be used), and maintenance doses of 30 mg/kg; 
PPD
PPD
PPD
PPD


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administration will be IV weekly during Cycle 1 and then every 2 weeks 
(Q2W) starting at Cycle 2 (cycle length is 28 days). Phase1b patients who 
have been on study for at least 8 weeks may be switched to the RP2DS, at 
the discretion of the Investigator. (Synopsis, Study Design Schema, 
Sections 1.5.1.2, 3.3, 3.4, 6.1, and Table 2 and Table 5). Based on emerging 
PK, pharmacodynamic and clinical data, the dosing regimen was changed to 
weekly dosing to improve patient convenience while maintaining potential 
efficacy and safety. 
• The ability to explore multiple Phase 2 dose regimens in the Phase 2 portion 
of the protocol is being added to potentially evaluate alternative dosing 
regimens that may maximize potential efficacy and patient convenience. 
Additional safety run-in dohorts will not be required for other doses. 
(Synopsis, Sections 1.5.1.2, 3.1, 3.3, 3.4, 3.5, 6.1,and Table 2 and Table 5).  
An initial futility analysis after 15 evaluable patients for each dosing regimen 
is included to evaluate potential efficacy differences to enable further patient 
enrollment (Section 11.4). 
• Modified the dose-limiting toxicity of Grade 3 infusion reaction to specify 
infusion reaction to Hu5F9-G4 or cetuximab (Section 3.2.4). 
• Modified the re-priming instructions (new Section 6.1.3).  Specified the timing 
and dose of Hu5F9-G4 required to obviate the effects of acute anemia that 
patients may experience after the first dose of drug.  For patients undergoing 
repriming, safety-related laboratory tests and procedures are required. 
• Modified the Dose Reductions and Delay Guidelines (Sections 6.1.3 and 
6.1.4). 
• Inclusion criterion 2b has been modified for subjects with KRAS wild-type 
CRC in Phase 2 in that patients must have only been refractory to (not 
relapsed from) prior anti- epidermal growth factor receptor (EGFR) therapy. 
Refractory is defined as failure to achieve an objective response, or 
progression during, any previous anti-EGFR containing regimen 
(monotherapy or in combination), or progression within 6 months of the last 


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dose. In addition, fluoropyrimidine was added to the criterion as a potential 
previous therapy (Synopsis, Section 4.1). 
• Inclusion criterion 7 was modified to reduce the calculated glomerular filtration 
rate from >40 mL/min/1.73 m2 to >30 mL/min/1.73 m2) (Synopsis, 
Section 4.1). 
• Exclusion criterion 12 was clarified to show that it is the IgG component of 
direct antiglobulin test (Synopsis, Section 4.2). 
• Reduced the number of estimated sites from 14 to 8 (Section 3.8). 
• Removal of sample collection for receptor occupancy studies in Phase 2 
(Section 7.11, Table 5 and Table 6; deleted previous Table 10).  At the 
current doses maximal RO appears to be achieved in the periphery; further 
collection in additional patients is unlikely to provide substantive scientific 
information or insights into dosing regimen, activity, or mechanism of action. 
• Specified that patients could discontinue either drug in the combination and 
continue participation in the study while receiving single-agent treatment 
(either Hu5F9-G4 or cetuximab) (Sections 3 and 6).  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 cetuximab alone, the patient may continue 
to participate in the study provided that other protocol stipulations are met. 
• Modified the secondary objectives and endpoints for Phase 1b and 2 to 
include disease control rate and time to progression (Synopsis, 
Sections 2.1.2, 2.2.2, and 11.3.1). 
• Added the secondary objective and endpoint of objective response rate 
(ORR) as determined by use of iRECIST (Response Evaluation Criteria in 
Solid Tumors guidelines for use in trials testing immunotherapeutics) 
(Synopsis, Sections 2.1.2, 2.2.2, 6.1, 7.9, 10.1, 10.3 [new], and 11.3.1, and 
References).  Incorporating iRECIST to address the potential for 
pseudoprogression and allowing for confirmation of tumor progression status. 


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• Added confirmed tumor progression according to iRECIST to the reasons for 
withdrawal from study treatments (Section 8.1).  In order to address the 
potential for pseudoprogression and more accurately confirm disease 
progression as the reason for treatment discontinuation in cases where this is 
applicable. 
• Specified that objective response rate (ORR) would be assessed in patients 
according to RECIST v 1.1 (primary endpoint) or iRECIST (secondary 
endpoint) (Synopsis, Sections 2.1.2, 2.2.2, 10.1, 10.3, and 11.3.1, and 
References).  In order to address the potential for pseudoprogression and 
allow confirmation of tumor progression status. 
• Correct an error in Table 10 (CD47 Receptor Occupancy Sample Time 
Points, Phase 1b [Table 9 in Amendment 2]). In the Cycle 1, Day 11, 72-hour 
time point, an errant footnote was shown; the footnote has been removed.  
Additionally, a new footnote (Footnote e) has been added that reads, “Sample 
to be collected from patients in non-loading dose cohort(s) only.” 
• Added collection of archival tumor tissue biopsy samples from sites, including 
block or unstained slides. 
Editorial changes and updates to style and formatting have been made to improve 
clarity and consistency throughout the document.  Changes in sections of the 
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 cetuximab 
Protocol Number:  5F9004 
Study Title:  Protocol Number 5F9004:  A Phase 1b/2 Trial of Hu5F9-G4 in 
Combination with Cetuximab in Patients with Solid Tumors and Advanced Colorectal 
Cancer 
Scientific Rationale and Background 
Metastatic colorectal cancer (CRC) is the second leading cause of cancer deaths in 
the United States (Siegel 2016).  Although screening strategies have started to 
reduce the overall colorectal cancer death rate, the development of advanced 
metastatic disease is still associated with poor long-term survival.  Systemic 
chemotherapy in combination with anti-epidermal growth factor receptor (EGFR) 
antibodies such as cetuximab and panitumumab have significantly improved 
prognosis in patients who have KRAS wild-type tumors (Lee 2015).  However, 
patients with KRAS mutations, which comprise over 40% of colorectal cancers 
(Vaughn 2011), do not respond to anti-EGFR antibody therapies (Allegra 2009).  
Patients with KRAS mutant metastatic colorectal cancer have a poor prognosis with 
limited available therapies if they fail front line chemotherapy.  The prognosis is also 
poor for patients with KRAS wild-type who progress during treatment and within 
6 months after anti-EGFR monoclonal antibody treatment.  Thus, additional 
therapies are needed to address this high unmet medical need in both patient 
populations. 
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 


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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.  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. 
Metastatic colorectal cancer patients with both KRAS mutant and KRAS wild-type 
tumors who are refractory to treatment with standard treatment regimens have 
limited options for effective treatment.  In patients with KRAS wild-type CRC who 
were refractory to all standard chemotherapy, cetuximab monotherapy significantly 
increases median survival over best supportive care from 4.8 months to 9.5 months 
(95% confidence interval [CI], 0.41 to 0.74; P < 0.001), but had no benefit for 
patients with KRAS mutated tumors (Karapetis 2008).  However, even in patients 
with KRAS wild-type CRC, the objective response rate to single-agent cetuximab 
was only 12.8%; thus, there is still a substantial unmet medical need for these 
patients.  Consequently, a monoclonal antibody targeting CD47 that enables 
phagocytosis and elimination of tumor cells and that demonstrates strong synergistic 
activity in combination with cetuximab in KRAS mutant and wild-type CRC would be 
an important therapeutic advance in the management of CRC patients. 
To date, no significant overlapping toxicities between Hu5F9-G4 and cetuximab 
have been observed.  The combination therapy of Hu5F9-G4 and cetuximab has 
shown strong preclinical evidence of activity in both RAS mutant and RAS wild-type 
CRC.  This combination creates the potential to address an unmet medical need for 
these patients.  The well-established tolerability of cetuximab and the manageable 
safety profile of Hu5F9-G4, together with the plans for rigorous safety monitoring in 
the Phase 1b part of this trial, suggests an acceptable risk-benefit profile for the 
advanced CRC patients enrolled in this study. 


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Study Objectives and Endpoints 
The study objectives and endpoints are outlined in Synopsis Table 1. 
Synopsis Table 1:  Study Objectives and Endpoints 
PRIMARY 
 
OBJECTIVES 
ENDPOINTS 
• 
To investigate the safety and tolerability, 
and to determine the recommended 
Phase 2 dose for Hu5F9-G4 in 
combination with cetuximab. 
• 
To evaluate overall response rate (ORR) 
of Hu5F9-G4 in combination with 
cetuximab in patients with KRAS mutant 
and KRAS wild-type CRC according to 
Response Evaluation Criteria in Solid 
Tumors (RECIST) v 1.1 
(Eisenhauer 2009). 
• 
Dose-limiting toxicities (DLTs) and 
adverse events (AEs) according to 
National Cancer Institute Common 
Terminology Criteria for Adverse 
Events (NCI CTCAE) v 4.03. 
• 
ORR using complete response (CR) 
+ partial response (PR) as defined by 
the investigator according to 
RECIST v 1.1. 
 
SECONDARY 
 
OBJECTIVES 
ENDPOINTS 
• 
To evaluate the pharmacokinetic (PK) 
profile of Hu5F9-G4 in combination with 
cetuximab. 
• 
To evaluate the immunogenicity of 
Hu5F9-G4 in combination with 
cetuximab. 
• 
To evaluate efficacy of Hu5F9-G4 in 
combination with cetuximab by the 
disease-control rate (DCR), duration of 
response (DOR), progression-free 
survival (PFS), overall survival (OS), and 
time to progression (TTP) for patients 
with KRAS mutant and KRAS wild-type 
CRC according to RECIST v 1.1 
(Eisenhauer 2009). 
• 
To evaluate the ORR of Hu5F9-G4 in 
combination with cetuximab in patients 
with KRAS mutant and KRAS wild-type 
CRC according to iRECIST guidelines 
(Seymour 2017). 
• 
Hu5F9-G4 concentration versus time 
measurements of Hu5F9-G4 in 
combination with cetuximab. 
• 
Anti-drug antibodies to Hu5F9-G4 
and cetuximab. 
• 
DCR, DOR, PFS, OS, and TTP as 
defined by the Investigator according 
to RECIST v 1.1. 
• 
ORR using iCR + iPR as defined by 
the Investigator according to the 
iRECIST guidelines. 
EXPLORATORY 
 
OBJECTIVES 
ENDPOINTS 
PPD


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Overall Study Design: 
This trial is an open label, multicenter Phase 1b/2 trial investigating the combination 
of Hu5F9-G4 and cetuximab in patients with solid tumor and patients with advanced 
CRC.  The study will be conducted in 2 parts: 
• Dose escalation Phase 1b open to patients with solid tumors 
• Phase 2 study with 2 treatment arms in patients with advanced/metastatic 
CRC whose tumors are either KRAS mutant or KRAS wild-type  
The Phase 1b dose escalation part of the study will be conducted using a standard 
3+3 dose escalation design to determine the maximum tolerated dose (MTD), if one 
exists, and to identify a recommended Phase 2 dose (RP2D) of Hu5F9-G4 in 
combination with cetuximab.  Up to 5 dose level cohorts are anticipated. 
PPD


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The Phase 2 part of the study will then incorporate a safety run-in by treating 
9 patients with KRAS wild-type tumors at the RP2D.  If the tolerability of the regimen 
is confirmed in CRC patients, the study will begin to accrue patients with advanced 
CRC who have KRAS mutant tumors and continue to accrue patients who have 
KRAS wild-type tumors and who are relapsed or refractory to an anti-EGFR antibody 
therapy.  Additional safety run-in cohorts will not be required if other doses are 
tested in Phase 2. 
Phase 1b Study Design 
In Cycle 1 of the Phase 1b part of the trial, the first dose escalation cohort will 
employ a Hu5F9-G4 priming dose of 1 mg/kg on Day 1 followed by 10-mg/kg 
maintenance doses on Days 8, 15, and 22.  Cetuximab will be administered at a 
reduced dose of 300 mg/m2 infused over 120-minutes on Day 8 followed by 
200 mg/m2 infusions given over 60 minutes on Days 15 and 22.  During Weeks 2-4, 
Hu5F9-G4 and cetuximab will be administered on the same day.  On all days on 
which both cetuximab and Hu5F9-G4 are given, cetuximab will be given first.  
Hu5F9-G4 will be given at least 1 hour after the cetuximab infusion is completed. 
In Cycle 2, patients in the second dose escalation cohort will receive the same 
priming and maintenance dose regimen of Hu5F9-G4.  If the starting dose of 
cetuximab in combination with Hu5F9-G4 is well tolerated the full standard dose of 
400 mg/m2 will be infused on Day 8 followed by 250 mg/m2 infusions on Days 15 
and 22.  The dose of cetuximab used in the combination will not exceed the 
recommended single-agent dose and will be given during Cycle 3 and subsequent 
cycles.  During Cycle 1, the weekly maintenance dose of Hu5F9-G4 will escalate to 
20 mg/kg for patients in dose Cohort 3, assuming this dose level continues to be 
safe and well tolerated in the ongoing single-agent Phase 1 trial (Study 
SCI-CD47-001).  Hu5F9-G4 will continue to be given weekly during subsequent 
cycles.  Additional dose escalation of Hu5F9-G4 may continue in subsequent dose 
cohorts including the exploration of a loading dose in Week 2; however, the dose of 
Hu5F9-G4 may not exceed the single-agent MTD defined in ongoing studies.  
The anticipated dose levels are shown in Synopsis Table 2. 


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For the Phase 1b part of the study, the maintenance dose of Hu5F9-G4 for the first 
cohort will be 10 mg/kg.  Dose escalation of the regimen will proceed through the 
designated dose levels, and decisions related to dose escalation will be based on 
the first 4 weeks of treatment in the current cohort, referred to as the “Dose-Limiting 
Toxicity (DLT) Assessment Period,” in conjunction with ongoing assessments for 
patients in prior cohorts who continued therapy beyond 4 weeks.  Decisions 
regarding additional cohorts to further refine the MTD or recommended Phase 2 
dose and schedule (RP2DS) will be made by the Clinical Trial Steering Committee 
(CTSC).  For example, the Hu5F9-G4 weekly maintenance dose schedule may be 
changed to every 2 or 3 weeks by the CTSC based on pharmacokinetic (PK) and 
clinical data review.  In addition, adding intermediate dose steps (e.g., a 
maintenance dose cohort of 15 mg/kg weekly) or selecting a 10- or 20-mg/kg loading 
dose may be explored in new dose cohorts if supported by emerging PK and clinical 
data. 


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Synopsis Table 2:  Phase 1b Dose Levels and Schedule 
Dose 
Cohort 
Drug/Dose 
(Intravenous) 
Dose Schedule 
(Day per 28-day Cycle) 
Cycle 1 
Cycle 2+ 
1 
Hu5F9-G4 1 mg/kg (prime) 
Day 1 
— 
Hu5F9-G4 10 mg/kg (maintenance) 
Day 8, 15, 22 
Day 1, 8, 15, 22 
Cetuximab 300 mg/m2 (load) 
Day 8 
Cetuximab 200 mg/m2 (maintenance) 
Day 15, 22 
Day 1, 8, 15, 22 
2 
Hu5F9-G4 1 mg/kg (prime) 
Day 1 
— 
Hu5F9-G4 10 mg/kg (maintenance) 
Day 8, 15, 22 
Day 1, 8, 15, 22 
Cetuximab 400 mg/m2 (load) 
Day 8 
 
Cetuximab 250 mg/m2 (maintenance) 
Day 15, 22 
Day 1, 8, 15, 22 
3 
Hu5F9-G4 1 mg/kg (prime) 
Day 1 
— 
Hu5F9-G4 20 mg/kg (maintenance) 
Day 8, 15, 22 
Day 1, 8, 15, 22 
Cetuximab 400 mg/m2 (load) 
Day 8 
 
Cetuximab 250 mg/m2 (maintenance) 
Day 15, 22 
Day 1, 8, 15, 22 
4 a 
Hu5F9-G4 1 mg/kg (prime) 
Day 1 
— 
Hu5F9-G4 30 mg/kg (maintenance) b 
Day 8, 15, 22 
Day 1, 8, 15, 22 
Cetuximab 400 mg/m2 (load) 
Day 8 
— 
Cetuximab 250 mg/m2 (maintenance) 
Day 15, 22 
Day 1, 8, 15, 22 
5 
Hu5F9-G4 1 mg/kg (prime) 
Day 1 
— 
Hu5F9-G4 45 mg/kg (maintenance) 
Day 8, 11,15, 22 
Cycle 2: Day 1, 8, 15, 22 
Cycle 3+: Day 1 and 15 
Cetuximab 400 mg/m2 (load) 
Day 8 
— 
Cetuximab 250 mg/m2 (maintenance) 
Day 15, 22 
Day 1, 8, 15, 22 
a The Hu5F9-G4 loading dose was not administered in Cohort 4. Potential loading dose cohort 
may be added if deemed necessary by the Clinical Trial Steering Committee (CTSC). 
b As recommended by CTSC, a 30-mg maintenance dose was administered in Cohort 4. 
Phase 1b Dose Escalation 
Dose escalation of Hu5F9-G4 and cetuximab in Phase 1b will follow a 3+3 study 
design.  Three to 6 patients may be enrolled in each dose cohort.  If none of the first 
3 patients experiences a DLT, dose escalation will proceed to the next higher dose 
cohort.  If 1 of the first 3 patients experiences a DLT, the cohort will be expanded to 
6 patients.  If more than 2 patients experience DLTs, the MTD dose level will have 
been exceeded, dose escalation will halt, and any additional patients will be treated 
at a lower dose level.  The MTD for the Phase 1b is the highest dose level at which 
at least 6 patients are evaluable and less than 33% of these patients experience a 
DLT.  The RP2D will be determined by the CTSC based on review of all available 


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safety, efficacy, PK, and pharmacodynamic data.  The first patient in each dose 
cohort must complete at least 1 week of treatment before additional patients may be 
enrolled in the cohort.  Subsequent patients may be enrolled simultaneously.  
The CTSC may expand the cohort by up to 6 additional patients for any dose level 
previously determined to be safe to collect additional safety and PK information and 
to confirm tolerability. 
Dose-Limiting Toxicity Definition 
Dose escalation decisions will be made by the CTSC based on the first 4 weeks of 
treatment for each patient, referred to as the “DLT Assessment Period.”  The last 
patient in a cohort must complete the DLT Assessment Period before new patients 
are escalated to a higher dose level. 
Patients assigned to a particular dose cohort in Phase 1b are considered evaluable 
for assessment of DLT if either of the following criteria are met in the DLT 
assessment period: 
• The patient experienced a DLT at any time after initiation of the first infusion of 
either Hu5F9-G4 or cetuximab. 
• The patient completed at least 4 infusions of Hu5F9-G4 and 2 infusions of 
cetuximab. 
Patients who withdraw before completing the 4-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. 
All toxicities will be graded according to the NCI CTCAE Version 4.03 (Appendix B), 
which provides additional guidance for AEs not specifically mentioned in CTCAE.  
A DLT is defined as any Grade 3 or greater AE that is assessed as related to study 
treatment that occurs during the 4-week DLT observation period.  DLTs apply only to 
patients in the Phase 1b part of the study. 


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The following are exceptions to the DLT definition and will NOT be considered a 
DLT: 
• Grade 3 anemia; however, Grade 3 hemolytic anemia that is medically 
significant, requiring hospitalization or prolongation of existing hospitalization, 
disabling, or limiting self-care activities of daily life (ADLs) 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. 
• Isolated Grade 3 electrolyte abnormalities that resolve to ≤ Grade 2 with 
supportive care within 1 week and are not associated with other clinically 
significant consequences. 
• Grade 3 elevation in alanine aminotransferase, aspartate aminotransferase, or 
alkaline phosphatase that resolves to ≤ Grade 2 with supportive care within 
1 week and is not associated with other clinically significant consequences. 
• Grade 3 nausea, vomiting, or diarrhea that resolves to ≤ Grade 2 with supportive 
care within 72 hours 
• Grade 3 fatigue that resolves to ≤ Grade 2 within 2 weeks on study. 
• Grade 3 Hu5F9-G4 or cetuximab-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) that resolve to ≤ Grade 2 or baseline within 
1 week 
• Grade 3 hypomagnesemia, that resolves to ≤ Grade 2 within 1 week 
• Grade 3 or 4 lymphopenia or leukopenia 
Phase 2 Study Design: 
Once the Phase 1b dose escalation phase of the trial is completed and an RP2D 
determined, the CTSC will open the Phase 2 part of the study.  Patients with 


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advanced CRC who have KRAS wild-type tumors will initially accrue until 9 patients 
are enrolled and have completed the DLT period.  If the DLT rate in this CRC 
population does not exceed 33%, accrual will begin for patients who have KRAS 
mutant tumors and continue to accrue for patients who have KRAS wild-type tumors.  
Additional safety run-in cohorts will not be required if other doses are tested in 
Phase 2.  Patients may be enrolled simultaneously without an observation time 
between patients.  After the appropriate number of initial stage patients in each arm 
have been enrolled and followed for at least 8 weeks, an efficacy and safety analysis 
will be performed as described in the Statistical Analysis Plan (SAP).  The CTSC will 
convene to review and approve proceeding with full accrual of either or both arms, or 
terminate either arm.  Full accrual in either arm may be opened earlier by the CTSC 
at any point at which sufficient anti-cancer activity is observed.  The CTSC may also 
approve further enrollment and exploration of additional alternate Phase 2 doses 
that may enhance efficacy. 
Based on review of safety, efficacy, and PK data available from Phase 1b, the 
planned Phase 2 dose and schedule of Hu5F9-G4 that will be used in the Phase 2 
part of this study and is shown in Synopsis Table 3. 
When both study drugs are given on the same visit day, Hu5F9-G4 will be 
administered at least 1 hour after the completion of the cetuximab administration. 
Starting with Cycle 2, the Day 8 and Day 22 dosing of Hu5F9-G4 has been removed 
(i.e., dosing is every 2 weeks [Q2W]).  Patients enrolled in the Phase 1b part of the 
study who have been on study for at least 8 weeks may have their dose revised to 
the RP2DS, at the discretion of the Investigator. 


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Synopsis Table 3:  Phase 2 Dose and Schedule 
Drug/Dose 
(Intravenous) 
Dose Schedule 
(Day per 28-day Cycle) 
Cycle 1 
Cycle 2 
Cycle 3+ 
Hu5F9-G4 1 mg/kg 
(prime) 
Day 1 
— 
—  
Hu5F9-G4 30 mg/kg 
(maintenance) 
Days 8, 15, and 22 
Days 1 and 15  
Days 1 and 15 
Cetuximab 400 mg/m2 
(load) 
Day 8 
— 
— 
Cetuximab 250 mg/m2 
(maintenance) 
Days 15 and 22 
Days 1, 8, 15, and 22 
Days 1, 8, 15, and 22 
Hu5F9-G4 1 mg/kg 
(prime) 
Day 1 
— 
—  
Hu5F9-G4 45 mg/kg 
(maintenance) a 
Days 8 ,11, 15, and 22 
Days 1, 8, 15, and 22 
Days 1 and 15 
Cetuximab 400 mg/m2 
(load) 
Day 8 
— 
— 
Cetuximab 250 mg/m2 
(maintenance) 
Days 15 and 22 
Days 1, 8, 15, and 22 
Days 1, 8, 15, and 22 
• 
a 
If recommended by the Clinical Trial Steering Committee, other doses and schedules may be 
tested in Phase 2 
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 Phase 2 trials, 
including evaluation of multiple Phase 2 doses, and interim efficacy analysis 
decisions.  The CTSC will meet at a minimum at the completion of each dosing 
cohort during dose escalation phase 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 
It is anticipated that this study will take approximately 42 months to complete. 
Patient participation will include screening, treatment, and follow-up.  Screening will 
last up to 30 days before first dose of study drugs, during which time the patient’s 
eligibility and baseline characteristics will be determined.  Treatment with study 
drugs may be continued until an unacceptable drug-related toxicity occurs, patient 
refusal, or until disease progression.  Post treatment, patients will be observed for 
disease progression and survival until death, withdrawal of consent, or the end of the 
study, whichever occurs first. 
Overview of Assessments 
Assessments will be performed according to the schedules provided in Protocol 
Section 7 (Table 4, Table 5, Table 6, Table 7, Table 8, Table 9, and Table 10). 
Planned Number of Patients 
An estimated 15 to 24 patients will be enrolled in Phase 1b, depending on dose 
escalation and expansion. 
Phase 2 includes 2 arms, one comprising patients with KRAS mutant CRC and the 
other comprising patients with KRAS wild-type CRC, in which enrollment in one or 
both arms may be modified based on emerging data.  A total of 88 patients 
(44 patients per arm) will be enrolled in Phase 2, assuming progression to Stage 2 
for both arms.   
Inclusion Criteria 
1. Adults ≥ 18 years old. 
2. Histological Diagnosis 
a. Phase 1b only: 
Histologically or cytologically confirmed advanced solid malignancy with 
an emphasis on CRC, head and neck, breast, pancreatic and ovarian 
cancers who have been treated with at least one regimen of prior systemic 


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therapy, or who refuse systemic therapy, and for which there is no curative 
therapy available. 
b. Phase 2: 
• KRAS Mutant CRC:  Histologically confirmed advanced KRAS mutant 
CRC who have progressed or are ineligible for fluoropyrimidine, 
irinotecan- and oxaliplatin-based chemotherapy 
OR 
• KRAS Wild-Type CRC:  Histologically confirmed advanced KRAS 
wild-type CRC who have progressed or are ineligible for 
fluoropyrimidine, irinotecan- and oxaliplatin-based chemotherapy and 
who are refractory to at least 1 prior systemic therapy that included an 
anti-EGFR antibody, such as cetuximab, panitumumab, or others.  
Patients should have disease progression during prior anti-EGFR 
therapy or within 6 months of the last day of treatment with the anti-
EGFR 
3. Eastern Cooperative Oncology Group (ECOG) Score 0-2. 
4. For the Phase 2 part only:  Disease that is measurable or assessable for 
response according to RECIST Version 1.1 Criteria. 
5. Laboratory measurements, blood counts: 
 Hemoglobin ≥ 9.5 g/dL. 
 Absolute neutrophil count (ANC) ≥ 1.0 × 109/mL. 
 Platelets ≥ 75 × 109/ mL. 
6. Laboratory measurements, hepatic function: 
 Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) < 5× 
upper limit of normal (ULN). 
 Bilirubin < 1.5X ULN or 3.0× ULN and primarily unconjugated if patient has 
a documented history of Gilbert’s syndrome or a genetic equivalent. 


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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. Negative urine or serum pregnancy test within 30 days before administration 
of Hu5F9-G4 for women of childbearing potential. 
9. Females of childbearing potential must be willing to use 1 effective method of 
contraception during the study and continue for 4 months after the last dose 
of Hu5F9-G4 and 6 months after the last dose of cetuximab. 
10. Males must be willing to use 1 effective method of contraception and refrain 
from sperm donation during the study and continue for 4 months after the last 
dose of Hu5F9-G4 and 6 months after the last dose of cetuximab, if the 
partner is a female of childbearing potential. 
11. Subject has provided informed consent. 
12. Must be willing and able to comply with the clinic visits and procedures 
outlined in the study protocol. 
13. Phase 2 only: 
Willing to consent to 1 mandatory pre-treatment and 1 on-treatment tumor 
biopsy, unless determined to not be feasible 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 active brain metastases (patients with stable treated central 
nervous system [CNS] lesions who are off corticosteroid and radiation therapy 
for at least 3 weeks are not considered active). 
2. Prior 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.  Localized non-central 
nervous system (CNS) radiotherapy, previous hormonal therapy with 
luteinizing hormone releasing hormone (LHRH) agonists for prostate cancer, 


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low-dose steroids (oral prednisone or equivalent ≤ 20 mg per day), and 
treatment with bisphosphonates and RANKL inhibitors are not criteria for 
exclusion. 
3. Prior treatment with CD47 or SIRPα-targeting agents. 
4. Known active or chronic hepatitis B or C infection or human 
immunodeficiency virus (HIV). 
5. Red blood cell (RBC) transfusion dependence, defined as requiring more than 
2 units of RBC transfusions 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. 
6. History of hemolytic anemia or Evans syndrome in the last 3 months. 
7. Phase 2 only: 
Second malignancy, except treated basal cell or localized squamous skin 
carcinomas, localized prostate cancer, or other malignancy for which 
treatment was completed at least 3 years ago and for which there is no 
evidence of recurrence. 
8. Hypersensitivity to the active substance or to murine proteins, or to any of the 
other excipients of cetuximab listed in Appendix A. 
9. Significant medical diseases or conditions, as assessed by the Investigators 
and Sponsor, that would substantially increase 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, uncontrolled diabetes 
mellitus, significant active infections, severely immunocompromised state, 
and congestive heart failure New York Heart Association (NYHA) Class II-IV. 
10. History of psychiatric illness or substance abuse likely to interfere with ability 
to comply with protocol requirements or give informed consent. 
11. Pregnancy or active breast feeding. 
12. Positive IgG component of the direct antiglobulin test (DAT). 


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Test Product, Dose, and Mode of Administration 
Hu5F9-G4 is a humanized IgG4 monoclonal antibody that binds to human CD47 and 
blocks its interaction with its receptor, enabling phagocytosis of human cancer cells.  
Hu5F9-G4 drug product is provided in a liquid dosage form intended for intravenous 
(IV) infusion, 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.   
Erbitux® (cetuximab) is a recombinant, human/mouse chimeric monoclonal antibody 
that binds specifically to the extracellular domain of the human EGFR.  Cetuximab is 
supplied at a concentration of 2 mg/mL as a 100 mg/50 mL, single-use vial or as a 
200 mg/100 mL, single-use vial as a sterile, injectable liquid containing no 
preservatives.  Cetuximab is formulated in a solution containing 8.48 mg/mL sodium 
chloride, 1.88 mg/mL sodium phosphate dibasic heptahydrate, 0.41 mg/mL sodium 
phosphate monobasic monohydrate, and Water for Injection, USP. 
Combination Therapy, Dose, and Mode of Administration 
Study Endpoints 
The study objectives and endpoints are outlined above in Synopsis Table 1. 
Statistical Methods and Analyses 
All analyses will be descriptive in nature.  Descriptive statistics will be provided for all 
safety and efficacy endpoints. 
All analyses will be conducted separately for patients in Phase 1b and Phase 2 parts 
of the study.  However, safety analyses may be conducted for patients in both Phase 
1b and Phase 2.  In addition, efficacy analyses will be conducted separately for the 
two cohorts in Phase 2. 
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 confidence intervals for primary and secondary efficacy 


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endpoints.  For time-to-event variables, the Kaplan-Meier (KM) estimates and 
corresponding two-sided 95% confidence intervals 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 SAP. 
Safety:  The statistical analysis of safety will be conducted for patients in the 
safety analysis set (SAF).  Safety variables to be examined include DLTs, 
treatment emergent adverse events (treatment-emergent adverse events 
[TEAEs]: AEs worsening or occurring during or after a patient’s first exposure to 
study drugs), vital signs, physical examinations, laboratory, receptor occupancy, 
and antidrug antibody assessments.  Adverse events will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA, Version 17.1 or later) and grouped 
by system organ class and preferred term. 
Efficacy:  Endpoints used in the efficacy analysis are ORR, DOR, DCR, PFS, 
OS, and TTP. 
Objective response is defined as CR+PR determined by RECIST v 1.1 (primary 
efficacy) and iCR+iPR determined by iRECIST (secondary efficacy) separately.  
ORR is defined as the proportion of patients with objective response in the 
Efficacy Analysis Set.  A sensitivity analysis of ORR will be conducted on the Per 
Protocol Analysis Set if more than 10% of patients in the Efficacy Analysis Set 
are excluded from the Per Protocol Analysis Set. 
Disease control is defined as CR + PR + stable disease (SD) determined by 
RECIST v 1.1. DCR is defined as the proportion of patients with disease control 
in the Efficacy Analysis Set. 
DOR is measured from when the first (objective) response is met (i.e., CR or PR) 
until the first date of objectively documented progressive disease.  Patients who 
do not have objectively progressive disease will be censored at their last 
documented progression-free date. 


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PFS is measured from dose initiation until the first date of objectively 
documented progression disease or death.  Patients who do not have objectively 
documented progression disease AND not died will be censored at their last 
documented progression-free date. 
OS is measured from dose initiation until death.  Patients who did not die will be 
censored at their last known alive date. 
TTP is measured from dose initiation until the first date of objectively 
documented progressive disease. Patients who do not have objectively 
documented progressive disease will be censored at their last documented 
progression-free date. 
Pharmacokinetics:  PK analysis will be conducted for Hu5F9-G4 and cetuximab 
using the PK Analysis Set (PAS).  Based on the distinct MOAs of Hu5F9-G4 and 
cetuximab, drug-drug PK interactions are not expected.  Thus, samples for PK 
analysis for cetuximab will be biobanked and will be analyzed based on CTSC 
recommendation.  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. 
Dose Proportionality:  The analysis of dose proportionality will be conducted for 
the area under the curve (AUC) and maximum concentration (Cmax) of Hu5F9-G4 
using a power model on log-transformed scale.  The log-transformed PK 
parameters will each be regressed onto a fixed factor for log (dose).  The 90% CI 
of the slope for each PK parameter will be computed from the model and 
presented in a summary table. 
Immunogenicity Analyses:  The rate and magnitude of anti-Hu5F9-G4 antibody 
positivity will be evaluated for individual patients, for all patients in the Phase 1b 
and 2 parts of the trial, and for the pooled patient population.  
 
 
PPD-


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Immunogenicity analysis will also be performed for cetuximab.  However, it is not 
expected that Hu5F9-G4 will impact the immunogenicity of cetuximab and vice 
versa. 
Pharmacodynamic and Biomarker Analyses:  Several pharmacodynamic and 
correlative studies will be conducted on patient samples, as described in the 
SAP.  
 
  
 
. 
Sample Size Determination: 
The total number of patients in this trial will include as many as 112 patients.  This 
sample size includes the Phase 1b and Phase 2 parts of the study.  In Phase 1b, a 
standard 3+3 dose escalation design will be used to explore the MTD of the 
investigational study drug combination in patients with solid tumors.  An estimated 
32 patients will be enrolled in Phase 1b, depending on dose escalation and 
expansion. 
Phase 2 includes 2 arms, one comprising patients with KRAS mutant CRC and the 
other comprising patients with KRAS wild-type CRC, in which enrollment in one or 
both arms may be modified based on emerging data.  A total of 88 patients 
(44 patients per arm) will be enrolled in Phase 2, assuming progression to Stage 2 
for both arms.  This sample size estimate was determined using a one-sided alpha 
level of 0.10 and a power of 0.80 based on a null hypothesis of 5% response rate 
compared to an alternative hypothesis of 15% for each cohort. 
 
PPD
PPD


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STUDY DESIGN SCHEMA 
Study 5F9004 A Phase 1b/2 Trial of Hu5F9-G4 in Combination with Cetuximab in Solid Tumor and Advanced 
Colorectal Cancer Patients 
 
R 
E 
Patient s with 
G 
advanced cancer 
who are not 
----. 
cand idates for 
s 
standard therapies 
T 
E 
R 
Part A (Phase lb)a 
(15-24 pts) 
All Comer Solid Tumor Patients 
Cohort One: 1;10' mg/kg 
Hu5F9-G4 w eekly + 300 t hen 
200 mg per m' cet uximab 
... 
Cohort Two: 1;10' mg/kg 
Hu5F9-G4 w eekly + 400 t hen 
250 mg perm' cet uximab w eekly 
... 
Cohort Three: 1;20 mg/kg 
Hu5F9-G4 w eekly + 400 t hen 
250 mg perm' cet uximab w eekly 
... 
Cohort Four': 1 mg/kg prime; 
30 mg/kg Hu5F9-G4 weekly + 
400 t hen 250 mg perm' 
cet uximab w eekly 
Cohort Five•: 1 mg/kg prime; 
45 mg/kg Hu5F9-G4 w eekly 
(Cycles 1 and 2) or biweekly 
(Cycle 3+) + 400 t hen 
250 mg perm' cet uximab weekly 
One cycle= Weekly x 4 treatment 
until progression 
RP2D 
----+ 
KRAS Wild -Type 
(up t o 44 ptsl 
Part B (Phase 2)b 
(up t o 88 pts) 
KRAS Mutant 
(up t o 44 pt s) 
Patients with advanced CRCwho are 
KRAS wild-type and are refractory to 
anti-EG FR mAb t herapy 
RP2D of Hu5F9-G4 + cetuximab w eekly 
Safety Run in 9 pt5 
Enroll addit ional 6 pt5 for t ot al of 15 pt5; 
2 cycles (8 w eeks) 
Pati ents with advanced CRCwith KRAS 
mutations wh o have progressed or are 
not cand idat es for oxaliplatin or 
Enroll 15 pt5; 2 cycles (8 w eeks) 
RP2D of Hu5F9G4 + cetuximab w eekly 
Abbrevi ations: CRC = col o rectalcancer; CTSC = Cl i nicall rial Steering Committee; E G FR = epidermal g roV1th f actor receptor; HO = nu II hypothesi!, H 1 = alternative hypothesis; mAb = monoclonal 
antibody; ORR = objective response; ?FS, progresion-free survival; pts= patients. 
• 3+3 dose escalation design. 
• An alternative dose regimen may be evaluated in additional patients as determined by th e CTSC. Once the initial saf ety run ~n in 9 patients VI ith KRAS VI ild-typ e cancer i s completed and d ecla-ed to 
be VI e II-tolerated, a run ~n phase VI ith 9 pat ients with KRAS VI ild-type tu mo rs VI ii no longer be required if alternative ?h ase 2 dose regimens a reg oing to be t ested. 
' 1, 10 mg/ kg rep resents a first priming dose of 1 mg/ kg follow ed by a maintenance dose of 10 mg/ kg of Hu 5 F9-G4 VI eekly th ereefter, sim ila-ly for 1,20 mg/ kg. 
• Cohort Four Hu SF9-G4 dosing regimen VI ii consist of 1 mg/ kg priming dose on Day 1, fallowed by VI e ekly maintenance doses of30 mg/ kg. 
• Cohort Five Hu5F9-G4 dosing regimen w illconsist of 1 mg/ kg priming dose on Day 1, followedbytwo 45 mg/ kg doses in Cycl e 1 W eek2 (Day Sand l oading doseDayll), and then w eekly 
ma intenancedosesof45 mg/ kg for the remai'lder ofCyclel and in Cycle 2, then biweekly (Daysl and 15) ma intenancedosesforCycl e 3+. 


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TABLE OF CONTENTS 
PROTOCOL APPROVAL PAGE ................................................................................ 3 
PROTOCOL ACCEPTANCE PAGE ........................................................................... 4 
SUMMARY OF CHANGES, AMENDMENT 3 ............................................................ 5 
PROTOCOL SYNOPSIS ............................................................................................ 9 
STUDY DESIGN SCHEMA ...................................................................................... 28 
TABLE OF CONTENTS ........................................................................................... 29 
LIST OF APPENDICES ............................................................................................ 33 
LIST OF TABLES ..................................................................................................... 33 
LIST OF FIGURES ................................................................................................... 33 
ABBREVIATIONS AND DEFINITIONS .................................................................... 34 
1. 
BACKGROUND ................................................................................................. 38 
1.1. 
Colorectal Cancer ................................................................................... 38 
1.2. 
Study Drug:  Hu5F9-G4, a CD47-blocking Antibody ............................... 38 
1.2.1. 
CD47 Biology ............................................................................ 38 
1.2.2. 
Hu5F9-G4:  A CD47-blocking Antibody ..................................... 40 
1.2.3. 
Preclinical Studies ..................................................................... 41 
1.2.4. 
Hu5F9-G4 Clinical Studies ........................................................ 43 
1.2.4.1. Summary of Hu5F9-G4 Clinical Safety .......................... 43 
1.2.4.2. Summary of Hu5F9-G4 Clinical Pharmacology ............. 45 
1.2.4.3. Summary of Hu5F9-G4 Clinical Efficacy ....................... 46 
1.2.4.4. Summary of Hu5F9-G4 Clinical Experience .................. 46 
1.3. 
Cetuximab ............................................................................................... 47 
1.4. 
Correlative Studies Background ............................................................. 48 
1.5. 
Starting Dose Rationale .......................................................................... 49 
1.5.1. 
Hu5F9-G4 Dose ........................................................................ 49 
1.5.1.1. Phase 1b Doses ............................................................ 49 
1.5.1.2. Phase 2 Dose ................................................................ 49 
1.5.2. 
Cetuximab Dose ........................................................................ 50 
1.6. 
Study Rationale and Risk-Benefit ........................................................... 50 
2. 
STUDY OBJECTIVES AND ENDPOINTS ......................................................... 52 
2.1. 
Study Objectives ..................................................................................... 52 
2.1.1. 
Primary Objectives .................................................................... 52 
2.1.2. 
Secondary Objectives................................................................ 52 
2.1.3. 
Exploratory Objectives ............................................................... 52 
2.2. 
Study Endpoints ...................................................................................... 52 
2.2.1. 
Primary Endpoints ..................................................................... 52 
2.2.2. 
Secondary Endpoints ................................................................ 53 
2.2.3. 
Exploratory Endpoints ............................................................... 53 
3. 
STUDY DESIGN ................................................................................................ 54 
3.1. 
Overall Study Design .............................................................................. 54 
3.2. 
Phase 1b Study Design .......................................................................... 54 
3.2.1. 
Phase 1b Dose Levels............................................................... 54 
3.2.2. 
Phase 1b Dose Escalation ........................................................ 56 


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3.2.3. 
Dose-limiting Toxicity Evaluation ............................................... 57 
3.2.3.1. Definition of DLT-evaluable Patients ............................. 57 
3.2.4. 
Definition of Dose-limiting Toxicity ............................................. 58 
3.3. 
Phase 2 Study Design ............................................................................ 59 
3.4. 
Planned Phase 2 Dose and Schedule .................................................... 59 
3.5. 
Clinical Trial Steering Committee ............................................................ 60 
3.6. 
Data Monitoring Committee .................................................................... 61 
3.7. 
Analysis of the Conduct of the Study ...................................................... 61 
3.8. 
Number of Sites ...................................................................................... 61 
3.9. 
Estimated Study Duration ....................................................................... 61 
4. 
SUBJECT SELECTION AND ENROLLMENT ................................................... 63 
4.1. 
Inclusion Criteria ..................................................................................... 63 
4.2. 
Exclusion Criteria .................................................................................... 65 
4.3. 
Patient Screening ................................................................................... 66 
4.4. 
Informed Consent Process ..................................................................... 66 
4.5. 
Registration Process ............................................................................... 67 
5. 
STUDY DRUG INFORMATION ......................................................................... 68 
5.1. 
Hu5F9-G4 ............................................................................................... 68 
5.1.1. 
Physical Description of Study Drug ........................................... 68 
5.2. 
Cetuximab ............................................................................................... 68 
5.2.1. 
Physical Description of Study Drug ........................................... 68 
6. 
TREATMENT PLAN .......................................................................................... 70 
6.1. 
Study Drug Administration Guidance:  Hu5F9-G4 and Cetuximab ......... 70 
6.1.1. 
Dosing ....................................................................................... 70 
6.1.2. 
Premedication ........................................................................... 71 
6.1.3. 
Repriming .................................................................................. 72 
6.1.4. 
Dose Delays, Dose Modifications, and Safety 
Management Guidelines ................................................................. 73 
6.1.4.1. Hu5F9-G4 ...................................................................... 73 
6.1.4.2. Cetuximab ..................................................................... 74 
6.1.5. 
Specific Safety Management Guidelines ................................... 77 
6.1.5.1. Cetuximab ..................................................................... 77 
6.1.5.2. Hu5F9-G4 ...................................................................... 78 
6.2. 
Post-therapy Follow-up and Patient Study Completion ........................... 83 
6.3. 
Defining the End of Trial ......................................................................... 84 
7. 
STUDY EVALUATIONS .................................................................................... 85 
7.1. 
Schedules of Assessment for Phase 1b and Phase 2 ............................ 85 
7.2. 
Assessment by Study Period .................................................................. 98 
7.2.1. 
Screening Assessments ............................................................ 98 
7.3. 
Description of Study Procedures ............................................................ 99 
7.3.1. 
Physical Examination/Visual Acuity ........................................... 99 
7.3.2. 
Vital Signs ................................................................................. 99 
7.3.3. 
Electrocardiographs................................................................. 100 
7.3.4. 
Type and Screen (ABO/Rh), DAT ........................................... 100 
7.3.5. 
Peripheral Blood Smear Assessment ...................................... 100 


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7.3.6. 
Pregnancy Test ....................................................................... 101 
7.3.7. 
Adverse Events ....................................................................... 101 
7.3.8. 
Concomitant Medications ........................................................ 101 
7.4. 
End of Treatment Visit .......................................................................... 101 
7.5. 
Safety Follow-up Visit ........................................................................... 102 
7.6. 
Long-term Follow-up ............................................................................. 103 
7.7. 
Survival Follow-up ................................................................................ 103 
7.8. 
Safety Assessments ............................................................................. 104 
7.9. 
Efficacy Assessments ........................................................................... 107 
7.10. Immunogenicity ..................................................................................... 107 
7.11. Pharmacodynamic and Biomarker Assessments .................................. 108 
8. 
STUDY DISCONTINUATION .......................................................................... 110 
8.1. 
Withdrawal of Patients from Study Drug Treatment .............................. 110 
8.2. 
Withdrawal of Patients from Study ........................................................ 110 
8.3. 
Study Termination ................................................................................. 111 
9. 
ASSESSMENT OF SAFETY ........................................................................... 112 
9.1. 
Safety Parameters and Definitions ....................................................... 112 
9.1.1. 
Adverse Event ......................................................................... 112 
9.1.2. 
Serious Adverse Event ............................................................ 112 
9.2. 
Methods and Timing for Capturing and Assessing Safety 
Parameters ........................................................................................... 113 
9.2.1. 
Adverse Event Reporting Period ............................................. 114 
9.2.2. 
Eliciting Adverse Events .......................................................... 114 
9.2.3. 
Assessment of Severity and Causality of Adverse Events ...... 115 
9.3. 
Procedures for Recording Adverse Events ........................................... 117 
9.3.1. 
Recording Adverse Events ...................................................... 117 
9.3.1.1. Diagnosis Versus Signs and Symptoms ...................... 117 
9.3.1.2. Adverse Events Occurring Secondary to Other 
Events ................................................................. 118 
9.3.1.3. Persistent or Recurrent Adverse Events...................... 118 
9.3.1.4. Abnormal Laboratory Values ....................................... 118 
9.3.1.5. Deaths ......................................................................... 119 
9.3.1.6. Worsening of Disease ................................................. 119 
9.3.1.7. Hospitalization, Prolonged Hospitalization, or 
Surgery ................................................................ 120 
9.3.1.8. Other Reportable Information ...................................... 120 
9.4. 
Expedited Reporting Requirements for Serious Adverse Events .......... 122 
9.4.1. 
Reporting Requirements for Fatal/Life Threatening SAEs 
Related to Investigational Products .............................................. 122 
9.4.2. 
Reporting Requirements for All SAEs...................................... 123 
9.5. 
Type and Duration of Follow-up of Patients after Adverse Events ........ 123 
10. MEASUREMENT OF EFFECT ........................................................................ 125 
10.1. Anti-cancer Effect ................................................................................. 125 
10.2. RECIST Version 1.1.............................................................................. 125 
10.2.1. Evaluation of Lesions .............................................................. 125 


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10.2.2. Assessment of Target Lesion Response ................................. 126 
10.2.3. Assessment of Non-target Lesions .......................................... 127 
10.2.4. Assessment of Evaluable rather than Measurable Disease .... 128 
10.3. iRECIST ................................................................................................ 128 
10.3.1. iRECIST Response Assessment ............................................. 128 
10.3.1.1. 
Confirming Progression ....................................... 128 
10.3.1.2. 
New Lesions ........................................................ 129 
10.3.1.3. 
Response and Stable Disease Duration 
(RECIST 1.1 and iRECIST) ................................. 132 
10.3.1.4. 
Methods of Measurement .................................... 133 
11. STATISTICAL CONSIDERATIONS ................................................................. 135 
11.1. Analysis Sets ........................................................................................ 135 
11.2. Sample Size Determination .................................................................. 136 
11.3. Statistical Methods ................................................................................ 136 
11.3.1. Efficacy Analyses .................................................................... 137 
11.3.1.1. 
Objective Response Rate .................................... 137 
11.3.1.2. 
Disease Control Rate .......................................... 137 
11.3.1.3. 
Duration of Response .......................................... 137 
11.3.1.4. 
Progression-free Survival .................................... 137 
11.3.1.5. 
Overall Survival ................................................... 138 
11.3.1.6. 
Time to Progression ............................................ 138 
11.3.2. Pharmacokinetic/Pharmacodynamics Analyses ...................... 138 
11.3.2.1. 
Pharmacokinetic Analyses .................................. 138 
11.3.2.2. 
Dose Proportionality ............................................ 140 
11.3.2.3. 
Immunogenicity Analyses .................................... 140 
11.3.2.4. 
Pharmacodynamic and Biomarker Analyses ....... 141 
11.3.3. Safety Analyses ....................................................................... 141 
11.3.3.1. 
Adverse Events ................................................... 142 
11.3.3.2. 
Analysis of Other Safety Endpoints ..................... 142 
11.4. Interim Analysis .................................................................................... 142 
12. ETHICAL AND ADMINISTRATIVE CONSIDERATIONS ................................. 144 
12.1. Compliance Statement.......................................................................... 144 
12.2. Investigator Responsibilities ................................................................. 144 
12.3. Institutional Review Board or Independent Ethics Committee .............. 145 
12.4. Informed Consent and Human Subject Protection ................................ 146 
12.5. Confidentiality ....................................................................................... 147 
12.6. Urgent Safety Measures ....................................................................... 148 
12.7. Serious Breaches and Fraud ................................................................ 148 
12.8. Study Monitoring ................................................................................... 149 
12.9. Audits and Inspections .......................................................................... 149 
12.10. Data Collection and Handling ............................................................... 149 
12.11. Maintenance of Source Documents and Record Retention .................. 151 
12.12. Long-term Retention of Samples for Additional Future Research ......... 152 
12.13. Financing and Insurance....................................................................... 153 
12.14. Publication Policy .................................................................................. 153 


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13. REFERENCES ................................................................................................ 154 
14. APPENDICES ................................................................................................. 157 
 
LIST OF APPENDICES 
Appendix A: Cetuximab (Erbitux®) Prescribing Information ................................... 157 
Appendix B: National Cancer Institute Common Terminology Criteria for 
Adverse Events ................................................................................. 158 
Appendix C: ECOG Performance Status ............................................................... 159 
Appendix D: RECIST Version 1.1 and iRECIST Guidelines .................................. 160 
Appendix E: Peripheral Smear Assessment ......................................................... 161 
LIST OF TABLES 
Table 1. 
Phase 1b Dose Levels and Schedule ................................................. 56 
Table 2. 
Phase 2 Dose and Schedule .............................................................. 60 
Table 3. 
Cetuximab Dose Modification Guidelines for Rash ............................. 77 
Table 4. 
Schedule of Assessments Phase 1b .................................................. 86 
Table 5. 
Schedule of Assessments Phase 2 .................................................... 90 
Table 6. 
Post-treatment Assessments, Phase 1b and Phase 2 ........................ 94 
Table 7. 
Pharmacokinetic Assessments, Phase 1b .......................................... 95 
Table 8. 
Pharmacokinetic Assessments, Phase 2 ............................................ 96 
Table 9. 
Correlative Studies Sample Time Points, Phases 1b and 2 ................ 96 
Table 10. 
CD47 Receptor Occupancy Sample Time Points, Phase 1b, 
Cohorts 1 to 4 ..................................................................................... 97 
Table 11. 
Analyte Listing .................................................................................. 105 
Table 12. 
Adverse Event Grade (Severity) Scale ............................................. 116 
Table 13. 
Causal Attribution Guidance ............................................................. 117 
Table 14 
Time-point iResponse ....................................................................... 130 
Table 15 
iRECIST Best Overall Response (iBOR) .......................................... 132 
Table 16. 
Noncompartmental Pharmacokinetic Parameters ............................. 139 
LIST OF FIGURES 
Figure 1. 
Preclinical Phagocytic and Anti-tumor Activity of Anti-CD47 
Antibodies ........................................................................................... 41 
Figure 2. 
Effect of Hu5F9-G4 in Combination with Cetuximab and 
Panitumumab in a Colon Cancer Xenograft Model ............................. 43 
 


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ABBREVIATIONS AND DEFINITIONS 
 
ABO 
any of the four blood groups A, B, AB, and O comprising the ABO system 
ADA 
antidrug antibodies 
AE 
adverse event 
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 
BUN 
blood urea nitrogen 
CBCs 
complete blood counts 
CFR 
Code of Federal Regulations 
CMV 
cytomegalovirus 
CNS 
central nervous system 
CR 
complete response 
CRC 
colorectal cancer 
CRF 
case report form (paper) 
CRO 
Clinical Research Organization 
CT 
computed tomography 
CTSC 
Clinical Trial Steering Committee 
CyTOF 
mass cytometry 
DAT 
direct antiglobulin test 
DCR 
disease-control rate 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
EAS 
Efficacy Analysis Set 
ECG 
electrocardiogram 
ECL 
electrochemiluminescent 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 


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EDC 
electronic data capture 
EGFR 
epidermal growth factor receptor 
ENS 
Enrolled Analysis Set 
EOT 
End of Treatment Visit 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
H0 
null hypothesis 
H1 
alternative hypothesis 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IHC 
immunohistochemistry 
ILD 
interstitial lung disease 
INR 
international normalized ratio 
IR 
immune response 
IRB 
Institutional Review Board 
iRECIST 
Response Evaluation Criteria in Solid Tumors guidelines for use in trials 
testing immunotherapeutics 
IUD 
intra-uterine device 
IUS 
intra-uterine hormone-releasing system 
IV 
intravenous 
IWRS 
interactive web response system 
kg 
kilogram 
KM 
Kaplan-Meier 
L 
liters 
LDH 
lactate dehydrogenase 
LHRH 
luteinizing-hormone releasing hormone 
LISS 
low ionic strength solution 
LSC 
leukemic stem cells 
LTFU 
long-term follow-up 
M1 
macrophages that suppress tumor progression 
M2 
macrophages that promote tumor progression 
mAb 
monoclonal antibody 


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MedDRA 
Medical Dictionary of Regulatory Activities 
mg 
milligram 
MHRA 
Medicines and Healthcare products Regulatory Agency (UK) 
MOA 
mechanism of action 
MSI 
microsatellite instability 
MTD 
maximum tolerated dose 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NDC 
National Drug Code 
NHL 
non-Hodgkin’s lymphoma 
NSG 
NOD/SCID/IL2R gamma null 
NYHA 
New York Heart Association 
ORR 
overall response rate 
OS 
overall survival 
PAS 
Pharmacokinetic Analysis Set 
PD 
progressive disease 
PeG 
polyethylene glycol 
PFS 
progression-free survival 
PPS 
Per-Protocol Analysis Set 
PK 
pharmacokinetic(s) 
PR  
partial response 
PRBC 
packed red blood cell (transfusions) 
PT 
prothrombin time 
Q2W 
every 2 weeks 
RBCs 
red blood cells 
REC 
research ethics committee 
RECIST 
Response Evaluation Criteria in Solid Tumors 
Rh 
Rhesus factor 
RO 
receptor occupancy 
RP2D 
recommended Phase 2 dose 
RP2DS 
recommended Phase 2 dose and schedule 
SAE 
serious adverse event 
SAF 
Safety Analysis Set 
SAP 
statistical analysis plan 
SD 
stable disease 


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SDV 
source data verification 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SIRPα 
signal regulatory protein alpha 
SOA 
schedule of assessments 
S-P 
Ser-Pro 
TEAE 
treatment-emergent adverse event 
TTP 
time to tumor progression 
ULN 
upper limit of normal 
WBCs 
white blood cells 
 


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1. BACKGROUND 
1.1. 
Colorectal Cancer 
Metastatic colorectal cancer (CRC) is the second leading cause of cancer deaths in 
the United States (Siegel 2016).  Although screening strategies have started to 
reduce the overall colorectal cancer death rate, the development of advanced 
metastatic disease is still associated with poor long-term survival.  Systemic 
chemotherapy in combination with anti-epidermal growth factor receptor (EGFR) 
antibodies such as cetuximab and panitumumab have significantly improved 
prognosis in patients who have KRAS wild-type tumors (Lee 2015).  However, 
patients with KRAS mutations, which comprise over 40% of colorectal cancers 
(Vaughn 2011), do not respond to anti-EGFR antibody therapies (Allegra 2009).  
Patients with KRAS mutant metastatic colorectal cancer have a poor prognosis with 
limited available therapies if they fail front line chemotherapy.  The prognosis is also 
poor for patients with KRAS wild-type who progress during treatment and within 
6 months after anti-EGFR monoclonal antibody treatment.  Thus, additional 
therapies are needed to address this high unmet medical need in both patient 
populations. 
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 of 
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 
depends on the relative balance of pro-phagocytic and anti-phagocytic inputs.  Most 
normal cells, apart from aging red blood cells (Okazawa 2005; Oldenborg 2000), 
lack expression of corresponding pro-phagocytic signals (Chao 2012; Jaiswal 2009; 


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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 colorectal 
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 carcinoma, prostate and colon cancer 
(Willingham 2012).  CD47 mRNA expression levels correlated with a worse 
progression-free and overall survival for patients with ovarian, gliomas and 
glioblastomas (Willingham 2012). 
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. 


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Most normal cells lack expression of pro-phagocytic signals and are unaffected by 
CD47 blockade.  Red blood cells (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.  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 phagocytotic 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. 
1.2.2. 
Hu5F9-G4:  A CD47-blocking Antibody 
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.  Based on this mechanism of action (MOA) and its potent 


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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 human solid tumors (breast, ovarian, colon, glioblastoma and others) 
(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 CRC laboratory 
models, anti-CD4 7 antibodies enhance the in vitro phagocytosis of CRC stem cells 
by macrophages and they also inhibit the in vivo growth of engrafted CRC tumor 
cells (Figure 1 ). 
Figure 1. 
Preclinical Phagocytic and Anti-tumor Activity of Anti-CD47 
Antibodies 
Colorectal Cancer Stem Cells 
Colon Cancer 
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patient-derived colorectal cancer stem cells by human peripheral blood-derived 
macrophages (squares) and NSG mouse bone marrow derived macrophages 
(circles). B6H12 is a murine anti-human CD47 monoclonal antibody that blocks 
CD47 binding to SIRPa. Right Panel: Anti-CD47 B6H12 antibody (500 µg daily IP) 
treatment inhibits the growth of engrafted human CRC tumors in an NSG mouse 
xenotransplantation model (Willingham 2012). 
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Anti-CD47 antibodies are also highly synergistic in combination with other anticancer 
therapies, including tumor-targeting monoclonal antibodies, such as cetuximab, 
panitumumab, rituximab, trastuzumab, and others (Chao 2010a; Chao 2011a; 
Willingham 2012; Liu 2015b; Forty Seven Inc., unpublished data).  Tumor targeting 
antibodies with active Fc effector functions can provide strong pro-phagocytic 
signals that augment the anti-tumor effects of Hu5F9-G4.  In preclinical studies in 
CRC, NOD/SCID/IL2R-gamma null (NSG) mice were subcutaneously implanted with 
UM8 colon cancer cells (EGFR+) transduced with GFP-luciferase-encoding 
lentivirus.  Twenty-eight days after engraftment, animals were treated with 
intraperitoneal injections of PBS control, cetuximab, panitumumab, Hu5F9-G4, or 
Hu5F9-G4 in combination with cetuximab or panitumumab (Figure 2; 
Study SU-RSR-16-002).  Animals were treated every other day (PBS, Hu5F9-G4) or 
weekly (cetuximab, panitumumab) for 16 weeks.  Treatment with Hu5F9-G4 alone in 
this model did not inhibit tumor growth, and treatment with cetuximab or 
panitumumab monotherapy stabilized tumor growth, but failed to produce a durable 
tumor remission.  However, significant tumor regression and durable remissions 
were observed in all mice treated with Hu5F9-G4 in combination with cetuximab or 
panitumumab.  Potent anti-tumor activity of Hu5F9-G4 in combination with 
cetuximab was also observed in both KRAS mutant and KRAS wild-type colorectal 
cancer models (Forty Seven Inc., unpublished data).  No evidence of systemic 
toxicity such as body weight loss was observed in these combination studies, 
although Hu5F9-G4 does not cross-react with murine CD47.  In summary, 
Hu5F9-G4 in combination with anti-EGFR antibodies such as cetuximab is a highly 
promising treatment for colorectal cancer, independent of RAS status.  


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Figure 2. 
Effect of Hu5F9-G4 in Combination with Cetuximab and 
Panitumumab in a Colon Cancer Xenograft Model 
Treatment 
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1.2.4. 
Hu5F9-G4 Clinical Studies 
1.2.4.1. 
Summary of Hu5F9-G4 Clinical Safety 
Hu5F9-G4 + 
Panitumumab 
The safety of Hu5F9-G4 is currently being evaluated in two ongoing Phase 1 trials. 
The initial first-in-human Phase 1 trial (SCI-CD47-001) started dosing patients on 
26 August 2014, and it is designed to determine the optimal dose and schedule of 
Hu5F9-G4 and to characterize its preliminary safety, pharmacokinetics (PK), and 
pharmacodynamics. This single institution study is enrolling patients with solid 
tumors and lymphomas; however, only solid tumor patients have been enrolled to 
date. A second Phase 1 trial (SCI-CD4 7-002) in relapsed refractory acute myeloid 
leukemia patients began dosing patients on 30 November 2015, and it is designed to 
define the maximum tolerated dose and to evaluate the safety, PK, and 
pharmacodynamics of Hu5F9-G4 in this patient population. 
In 17 patients treated with Hu5F9-G4 (16 with solid tumors as of 4 February 2016, 
and 1 patient with AML as of 31 December 2015), Hu5F9-G4 has been 
well tolerated. The most common treatment-associated effects related to the 
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targeting of CD47 on erythrocytes, with anemia and RBC agglutination being most 
prominent.  Other common treatment-related adverse events (AEs) include mild 
headache, fatigue, nausea, photopsia, urine discoloration, low back pain, and 
abdominal pain.  Common drug-related abnormal laboratory findings include 
transient reticulocytosis, spherocytosis, hyperbilirubinemia, D-dimer elevation, and 
decreased haptoglobin.  The majority of these findings occur following the first 
infusion, with very few study drug-related toxicities reported beyond the first cycle.  
In patients with solid tumors, the recommended priming dose of 1 mg/kg of 
Hu5F9-G4 was defined by the dose-limiting toxicities (DLTs) of acute abdominal 
pain and headache associated with hemagglutination.  However, using a priming 
and maintenance dose schedule in these patients has allowed for the further 
escalation of the maintenance dose to 10-20 mg/kg. 
As expected, the most common, clinically relevant toxicity is an acute anemia 
manifested as a 1- to 2-g/dL fall in hemoglobin observed during the first 1 to 2 weeks 
of treatment.  In solid tumor patients, this is followed by a compensatory 
reticulocytosis and a gradual return to baseline by Week 3 or 4 despite continued 
dosing.  These clinical observations are completely consistent with the known MOA 
of Hu5F9-G4 and the physiologic role of CD47 in regulating the turnover of aging 
erythrocytes.  Other associated laboratory abnormalities including reticulocytosis, 
spherocytosis, transient hyperbilirubinemia (predominantly unconjugated), and 
decreased haptoglobin are all indicative of extravascular hemolysis consistent with 
phagocytic removal of RBCs due to blockade of CD47.  No solid tumor patient has 
required a blood transfusion; however, the single patient enrolled to date in the AML 
Phase 1 study (SCI-CD47‐002) was transfusion-dependent prior to study entry and 
has received frequent RBC transfusions without problems throughout the first 
5 weeks on study. 
A second treatment-related effect on erythrocytes is hemagglutination, which is 
presumed to result from the direct interaction of Hu5F9-G4 with CD47 on red blood 
cells.  In Part A of the solid tumor Phase 1 study (SCI‐CD47‐001), hemagglutination 
was observed on peripheral blood smears in 8 out of 11 patients, typically within 


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24 hours of study drug administration.  Although D-dimer elevation was also 
common, there was no evidence of disseminated intravascular coagulation, nor were 
there any signs of thrombocytopenia, coagulopathy, microangiopathy, 
thromboembolic disease, or other clinical sequelae associated with the 
hemagglutination findings.  An asymptomatic solitary cotton wool spot was noted on 
retinal photographic examination in 1 solid tumor patient, but this was not associated 
with any hemagglutination and subsequently resolved. 
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 2 ongoing Phase 1 clinical studies, dose escalation is continuing and efficacy 
data from patients with systemic Hu5F9-G4 exposures in the range associated with 
preclinical activity is still pending.  No objective responses have been observed in 
10 of the 13 patients with solid tumors who were evaluable for tumor response at the 
time of data cutoff in the ongoing dose escalation solid tumor Phase 1 study 
(SCI-CD47-001).  Two patients with adenoid cystic carcinomas had stable disease 
for 33 and 72 weeks.  In Study SCI‐CD47‐002, the single patient with AML treated 
thus far has had stable disease based on a Day 25 bone marrow evaluation and 
remains on study with stable disease after 5 weeks of treatment. 
1.2.4.4. 
Summary of Hu5F9-G4 Clinical Experience 
In summary, the expected adverse effects of anemia and hemagglutination have 
been observed in solid tumor and AML patients treated with Hu5F9-G4, but the 
overall safety profile to date is manageable and consistent with preclinical toxicology 
studies.  All non-hematological Hu5F9-G4-associated toxicities have been transient 
and easy to manage.  Supportive care with frequent RBC transfusions has been 
safely and successfully administered to an AML patient who was concurrently 
treated with Hu5F9-G4.  Furthermore, implementation of a priming and maintenance 
dose strategy, coupled with the extension of the priming infusion duration to 3 hours, 
appear to substantially modulate the hematological toxicities of this novel agent, 


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thereby allowing dose escalation to continue in the ongoing Phase 1 studies.  
Nonclinical studies with Hu5F9-G4 in combination with anti-EGFR antibodies have 
been conducted in colorectal xenograft mouse models.  No evidence of systemic 
toxicity, such as body weight loss, was observed in these combinations studies; 
however, Hu5F9-G4 does not cross-react with murine CD47 (Forty Seven Inc., 
unpublished data). 
1.3. 
Cetuximab 
Cetuximab (Erbitux®) is a commercially available chimeric mouse/human IgG1 
kappa monoclonal antibody that targets EGFR (Appendix A).  Its principal 
mechanism of action is through down regulation of the EGFR/KRAS/RAF/MAPK 
signaling pathway; although antibody-dependent cellular cytotoxicity may also be 
relevant (Fan 1993; Kurai 2007).  It is approved for the treatment of KRAS wild-type 
CRC as a first-line agent and in later lines of therapy.  It is not indicated for treatment 
of RAS-mutant colorectal cancers.  Cetuximab is also approved for the treatment of 
squamous cell carcinoma of the head and neck in combination with radiation for 
locally advanced disease, or with platinum-based chemotherapy plus 5-fluorouracil 
for recurrent/metastatic disease.  The most commonly observed adverse reactions 
associated with cetuximab treatment include cutaneous reactions (including rash, 
pruritus, and nail changes), headache, diarrhea, and infection.  The most serious 
adverse reactions with cetuximab are infusion reactions, cardiopulmonary arrest, 
dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung 
disease, and pulmonary embolus.  Cetuximab exhibits non-linear PK with 
decreasing clearance observed at higher doses.  After the administration of the 
recommended dose regimen of 400 mg/m2 initial loading dose, followed by 
250 mg/m2 weekly doses, concentrations of cetuximab reached steady-state levels 
by the third weekly infusion.  The mean half-life of cetuximab is approximately 
112 hours (range 63–230 hours) (Appendix A). 


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1.4. 
Correlative Studies Background 
Blockade of the CD47-SIRPα signaling axis on tumor cells by a monoclonal 
anti-CD47 antibody leads 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 intratumoral 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 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 


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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.  Indeed, 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. 
1.5. 
Starting Dose Rationale 
1.5.1. 
Hu5F9-G4 Dose 
1.5.1.1. 
Phase 1b Doses 
In the Phase 1b part of the trial of Hu5F9-G4 in patients with solid tumors 
(SCI-CD47-001), the safety and PK of a 1-mg/kg priming dose followed by weekly 
maintenance doses of 10 ,20, 30, and 45 mg/kg weekly were to be explored 
(Forty Seven Inc., unpublished data).  Pharmacokinetic modeling suggests that 
these dose levels should generate circulating Hu5F9-G4 drug concentrations that 
exceed those associated with anti-tumor efficacy in preclinical models.  In the 
current Phase 1b trial, the first dose escalation cohort will receive 1 mg/kg of 
Hu5F9-G4 as a priming dose followed by weekly 10-mg/kg maintenance doses.  
This starting dose of up to 45 mg/kg weekly has been declared safe and well 
tolerated in the ongoing solid tumor single-agent Phase 1 trial.  The dose of 
Hu5F9-G4 in combination with cetuximab will not exceed the maximum tolerated 
dose (MTD) for single-agent Hu5F9-G4 defined in the ongoing solid tumor Phase 1 
trial (SCI-CD47-001). 
1.5.1.2. 
Phase 2 Dose 
The Clinical Trial Steering Committee (CTSC) has determined, based on the 
aggregate safety, efficacy, PK, and pharmacodynamic data obtained in the 
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portion of this study will be as follows:  A priming dose of 1 mg/kg and maintenance 
doses of 30 mg/kg; administration will be intravenous (IV) weekly during Cycle 1, 
and then every 2 weeks (Q2W) starting at Cycle 2 (cycle length is 28 days).  Based 
on review of ongoing dosing data, the CTSC may recommend testing of multiple 
doses and schedules in Phase 2, including higher doses of Hu5F9. 
1.5.2. 
Cetuximab Dose 
Because the adverse effect profile of the combination of Hu5F9-G4 plus cetuximab 
is not known, a moderately reduced starting dose of cetuximab will be utilized in 
combination with Hu5F9-G4 to evaluate the initial safety of the combination regimen.  
Cetuximab will be started at a dose of 300 mg/m2 initially followed by 200 mg/m2 
weekly in combination with Hu5F9-G4, which is a 25% and 20% reduction from the 
approved full cetuximab dose (400 mg/m2 administered as a 120-minute intravenous 
infusion followed by 250 mg/m2 weekly, infused over 60 minutes).  If the starting 
dose in combination with Hu5F9-G4 is well tolerated, the dose of cetuximab will be 
escalated to the full recommended single-agent dose in the second dose cohort.  
The dose of Hu5F9-G4 will be escalated to the 20-mg/kg maintenance level only 
after the cetuximab dose is increased. 
1.6. 
Study Rationale and Risk-Benefit 
Metastatic colorectal cancer patients with both KRAS mutant and KRAS wild-type 
tumors who are refractory to standard treatment regimens have limited options for 
effective treatment.  In patients with KRAS wild-type CRC who were refractory to all 
standard chemotherapy, cetuximab monotherapy significantly increases median 
survival over best supportive care from 4.8 months to 9.5 months (95% confidence 
interval, 0.41 to 0.74; P < 0.001), but had no benefit for patients with KRAS mutated 
tumors (Karapetis 2008).  However, even in patients with KRAS wild-type CRC, the 
objective response rate to single-agent cetuximab was only 12.8%; thus, there is still 
a substantial unmet medical need for these patients.  Consequently, a monoclonal 
antibody targeting CD47 that enables phagocytosis and elimination of tumor cells 
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KRAS mutant and wild-type CRC would be an important therapeutic advance in the 
management of CRC patients. 
To date, no significant overlapping toxicities between Hu5F9-G4 and cetuximab 
have been observed.  Single-agent toxicity data are summarized in Section 1.2.4.1 
for Hu5F9-G4 and in Section 1.3 for cetuximab.  The safety risk of the proposed 
combination is not anticipated to be substantially increased beyond that associated 
with single-agent therapies.  However, because the preclinical safety experience 
with this combination is limited, reduced starting doses of both Hu5F9-G4 and 
cetuximab will be utilized in the initial dose escalation Phase 1b part of this trial.  
The AE profile of this combination will be closely monitored using a standard 3+3 
study design prior to further escalation. 
The combination therapy of Hu5F9-G4 and cetuximab has shown strong preclinical 
evidence of activity in both RAS mutant and RAS wild-type CRC.  This combination 
creates the potential to address an unmet medical need for these patients.  
The well-established tolerability of cetuximab and the manageable safety profile of 
Hu5F9-G4, together with the plans for rigorous safety monitoring in the Phase 1b 
part of this trial, suggests an acceptable risk-benefit profile for the advanced CRC 
patients enrolled in this study. 


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2. STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objectives 
• To investigate the safety and tolerability, and to determine the recommended 
Phase 2 dose for Hu5F9-G4 in combination with cetuximab. 
• To evaluate ORR of Hu5F9-G4 in combination with cetuximab in patients with 
KRAS mutant and KRAS wild-type CRC according to RECIST v 1.1 
(Eisenhauer 2009). 
2.1.2. 
Secondary Objectives 
• To evaluate the PK profile of Hu5F9-G4 in combination with cetuximab. 
• To evaluate the immunogenicity of Hu5F9-G4 in combination with cetuximab. 
• To evaluate efficacy of Hu5F9-G4 in combination with cetuximab by the 
disease-control rate (DCR), DOR, PFS, OS, and TTP for patients with KRAS 
mutant and KRAS wild-type CRC according to RECIST v 1.1 (Eisenhauer 2009). 
• To evaluate the ORR of Hu5F9-G4 in combination with cetuximab in patients with 
KRAS mutant and KRAS wild-type colorectal cancer (CRC) according to 
iRECIST guidelines (Seymour 2017). 
2.1.3. 
Exploratory Objectives 
2.2. 
Study Endpoints 
2.2.1. 
Primary Endpoints 
The primary endpoints for this study are: 
• Dose-limiting toxicities (DLTs) in Phase 1b, and AEs according to National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
PPD


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Version 4.03. 
• ORR using CR + PR as defined by the investigator according to the RECIST 
Version 1.1 Criteria. 
2.2.2. 
Secondary Endpoints 
The secondary endpoints for this study are: 
• Hu5F9-G4 concentration versus time measurements of Hu5F9-G4 in 
combination with cetuximab. 
• Anti-drug antibodies to Hu5F9-G4 and cetuximab. 
• DCR, DOR, PFS, OS, and TTP as defined by the Investigator according to the 
RECIST Version 1.1 Criteria. 
• ORR using iCR + iPR as defined by the Investigator according to the iRECIST 
guidelines. 
2.2.3. 
Exploratory Endpoints 
PPD


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3. STUDY DESIGN 
3.1. 
Overall Study Design 
This trial is an open label, multicenter Phase 1b/2 trial investigating the combination 
of Hu5F9-G4 and cetuximab in patients with solid tumor and patients with advanced 
CRC.  The study will be conducted in 2 parts: 
1. Dose escalation Phase 1b open to patients with solid tumors 
2. Phase 2 study with 2 treatment arms in patients with advanced/metastatic 
CRC whose tumors are either KRAS mutant or KRAS wild-type  
The Phase 1b dose escalation part of the study will be conducted using a standard 
3+3 dose escalation design to determine the MTD, if one exists, and to identify a 
recommended Phase 2 dose (RP2D) of Hu5F9-G4 in combination with cetuximab.  
Up to 5 dose level cohorts are anticipated. 
The Phase 2 part of the study will then incorporate a safety run-in by treating 
9 patients with KRAS wild-type tumors at the RP2D.  If the tolerability of the regimen 
is confirmed in CRC patients, the study will begin to accrue patients with advanced 
CRC who have KRAS mutant tumors and continue to accrue patients who have 
KRAS wild-type tumors and who are relapsed or refractory to an anti-EGFR antibody 
therapy.  Additional safety run-in cohorts will not be required if other doses are 
tested in Phase 2.  A total of up to 88 evaluable patients (44 patients with KRAS 
wild-type and 44 patients with KRAS mutant CRC) will be enrolled in the Phase 2 
part.  Patients who do not receive at least 2 doses of Hu5F9-G4 (of which at least 
1 of the doses is a maintenance dose) may be replaced. 
3.2. 
Phase 1b Study Design 
3.2.1. 
Phase 1b Dose Levels 
In Cycle 1 of the Phase 1b part of the trial, the first dose escalation cohort will 
employ a Hu5F9-G4 priming dose of 1 mg/kg on Day 1 followed by 10-mg/kg 
maintenance doses on Days 8, 15, and 22.  Cetuximab will be administered at a 
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200 mg/m2 infusions given over 60 minutes on Days 15 and 22.  During Weeks 2-4, 
Hu5F9-G4 and cetuximab will be administered on the same day.  On all days on 
which both cetuximab and Hu5F9-G4 are given, cetuximab will be given first.  
Hu5F9-G4 will be given at least 1 hour after the cetuximab infusion is completed. 
In Cycle 2, patients in the second dose escalation cohort will receive the same 
priming and maintenance dose regimen of Hu5F9-G4.  If the starting dose of 
cetuximab in combination with Hu5F9-G4 is well tolerated the full standard dose of 
400 mg/m2 will be infused on Day 8 followed by 250 mg/m2 infusions on Days 15 
and 22.  The dose of cetuximab used in the combination will not exceed the 
recommended single-agent dose and will be given during Cycle 3 and subsequent 
cycles.  During Cycle 1, the weekly maintenance dose of Hu5F9-G4 will escalate to 
20 mg/kg for patients in dose Cohort 3, assuming this dose level continues to be 
safe and well tolerated in the ongoing single-agent Phase 1 trial (Study 
SCI-CD47-001).  Hu5F9-G4 will continue to be given weekly during subsequent 
cycles.  Additional dose escalation of Hu5F9-G4 may continue in subsequent dose 
cohorts including the exploration of a loading dose in Week 2; however, the dose of 
Hu5F9-G4 may not exceed the single-agent MTD defined in ongoing studies.  
The anticipated dose levels are shown in Table 1. 
For the Phase 1b part of the study, the maintenance dose of Hu5F9-G4 for the first 
cohort will be 10 mg/kg.  Dose escalation of the regimen will proceed through the 
designated dose levels, and decisions related to dose escalation will be based on 
the first 4 weeks of treatment in the current cohort, referred to as the “Dose-Limiting 
Toxicity (DLT) Assessment Period,” in conjunction with ongoing assessments for 
patients in prior cohorts who continued therapy beyond 4 weeks.  Decisions 
regarding additional cohorts to further refine the MTD or recommended Phase 2 
dose and schedule (RP2DS) will be made by the CTSC.  For example, the 
Hu5F9-G4 weekly maintenance dose schedule may be changed to every 2 or 
3 weeks by the CTSC based on PK and clinical data review.  In addition, adding 
intermediate dose steps (e.g., a maintenance dose cohort of 15 mg/kg weekly) or 


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selecting a 10- or 20-mg/kg loading dose may be explored in new dose cohorts if 
supported by emerging PK and clinical data. 
Table 1. 
Phase 1b Dose Levels and Schedule 
Dose 
Cohort 
Drug/Dose 
(Intravenous) 
Dose Schedule 
(Day per 28-day Cycle) 
Cycle 1 
Cycle 2+ 
1 
Hu5F9-G4 1 mg/kg (prime) 
Day 1 
— 
Hu5F9-G4 10 mg/kg (maintenance) 
Day 8, 15, 22 
Day 1, 8, 15, 22 
Cetuximab 300 mg/m2 (load) 
Day 8 
Cetuximab 200 mg/m2 (maintenance) 
Day 15, 22 
Day 1, 8, 15, 22 
2 
Hu5F9-G4 1 mg/kg (prime) 
Day 1 
— 
Hu5F9-G4 10 mg/kg (maintenance) 
Day 8, 15, 22 
Day 1, 8, 15, 22 
Cetuximab 400 mg/m2 (load) 
Day 8 
 
Cetuximab 250 mg/m2 (maintenance) 
Day 15, 22 
Day 1, 8, 15, 22 
3 
Hu5F9-G4 1 mg/kg (prime) 
Day 1 
— 
Hu5F9-G4 20 mg/kg (maintenance) 
Day 8, 15, 22 
Day 1, 8, 15, 22 
Cetuximab 400 mg/m2 (load) 
Day 8 
 
Cetuximab 250 mg/m2 (maintenance) 
Day 15, 22 
Day 1, 8, 15, 22 
4 a 
Hu5F9-G4 1 mg/kg (prime) 
Day 1 
— 
Hu5F9-G4 30 mg/kg (maintenance) b 
Day 8, 15, 22 
Day 1, 8, 15, 22 
Cetuximab 400 mg/m2 (load) 
Day 8 
— 
Cetuximab 250 mg/m2 (maintenance) 
Day 15, 22 
Day 1, 8, 15, 22 
5 
Hu5F9-G4 1 mg/kg (prime) 
Day 1 
— 
Hu5F9-G4 45 mg/kg (maintenance) 
Day 8, 15, 22 
Cycle 2: Day 1, 8, 15, 22 
Cycle 3+: Day 1 and 15 
Hu5F9-G4 45 mg/kg (loading) 
Day 11 
 
Cetuximab 400 mg/m2 (load) 
Day 8 
— 
Cetuximab 250 mg/m2 (maintenance) 
Day 15, 22 
Day 1, 8, 15, 22 
a 
The Hu5F9-G4 loading dose was not administered in Cohort 4. Potential loading dose 
cohort may be added if deemed necessary by the Clinical Trial Steering Committee 
(CTSC). 
b 
As recommended by CTSC, a 30-mg maintenance dose was administered in Cohort 4. 
 
3.2.2. 
Phase 1b Dose Escalation 
Dose escalation of Hu5F9-G4 and cetuximab in Phase 1b will follow a 3+3 study 
design.  Three to 6 patients may be enrolled in each dose cohort.  If none of the first 
3 patients experiences a DLT, dose escalation will proceed to the next higher dose 
cohort.  If 1 of the first 3 patients experiences a DLT, the cohort will be expanded to 


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6 patients.  If more than 2 patients experience DLTs, the MTD dose level will have 
been exceeded, dose escalation will halt, and any additional patients will be treated 
at a lower dose level.  The MTD for the Phase 1b is the highest dose level at which 
at least 6 patients are evaluable and less than 33% of these patients experience a 
DLT.  The RP2D will be determined by the CTSC (Section 3.5) based on review of 
all available safety, efficacy, PK, and pharmacodynamic data.  The first patient in 
each dose cohort must complete at least 1 week of treatment before additional 
patients may be enrolled in the cohort.  Subsequent patients may be enrolled 
simultaneously.  The CTSC may expand the cohort by up to 6 additional patients for 
any dose level previously determined to be safe to collect additional safety and PK 
information and to confirm tolerability.  
3.2.3. 
Dose-limiting Toxicity Evaluation 
Dose escalation decisions will be made by the CTSC based on the first 4 weeks of 
treatment for each patient, referred to as the “Dose-Limiting Toxicity (DLT) 
Assessment Period.”  The last patient in a cohort must complete the DLT 
Assessment Period before new patients are escalated to a higher dose level. 
3.2.3.1. 
Definition of DLT-evaluable Patients 
Patients assigned to a particular dose cohort in Phase 1b are considered evaluable 
for assessment of DLT if either of the following criteria are met in the DLT 
assessment period: 
• The patient experienced a DLT at any time after initiation of the first infusion of 
either Hu5F9-G4 or cetuximab. 
• The patient completed at least 4 infusions of Hu5F9-G4 and 2 infusions of 
cetuximab. 
Patients who withdraw before completing the 4-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. 


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3.2.4. 
Definition of Dose-limiting Toxicity 
All toxicities will be graded according to the NCI CTCAE Version 4.03 (Appendix B).  
A DLT is defined as any Grade 3 or greater AE that is assessed as related to study 
treatment that occurs during the 4-week DLT observation period.  DLTs apply only to 
patients in the Phase 1b part of the study. 
The following are exceptions to the DLT definition and will NOT be considered a 
DLT: 
• Grade 3 anemia; however, Grade 3 hemolytic anemia that is medically 
significant, requiring hospitalization or prolongation of existing hospitalization, 
disabling, or limiting self-care activities of daily life (ADLs) 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. 
• Isolated Grade 3 electrolyte abnormalities that resolve to ≤ Grade 2 with 
supportive care within 1 week and are not associated with other clinically 
significant consequences. 
• Grade 3 elevation in alanine aminotransferase, aspartate aminotransferase, or 
alkaline phosphatase that resolves to ≤ Grade 2 with supportive care within 
1 week and is not associated with other clinically significant consequences. 
• Grade 3 nausea, vomiting, or diarrhea that resolves to ≤ Grade 2 with supportive 
care within 72 hours 
• Grade 3 fatigue that resolves to ≤ Grade 2 within 2 weeks on study. 
• Grade 3 Hu5F9-G4 or cetuximab-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) that resolve to ≤ Grade 2 or baseline within 
1 week 
• Grade 3 hypomagnesemia, that resolves to ≤ Grade 2 within 1 week 


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• Grade 3 or 4 lymphopenia or leukopenia 
3.3. 
Phase 2 Study Design 
Once the Phase 1b dose escalation phase of the trial is completed and an RP2D 
determined, the CTSC will open the Phase 2 part of the study.  Patients with 
advanced CRC who have KRAS wild-type tumors will initially accrue until 9 patients 
are enrolled and have completed the DLT period.  If the DLT rate in this CRC 
population does not exceed 33%, accrual will begin for patients who have KRAS 
mutant tumors and continue to accrue for patients who have KRAS wild-type tumors.  
Patients may be enrolled simultaneously without an observation time between 
patients.  Patients who do not receive at least 2 doses of Hu5F9-G4 (of which at 
least 1 of the doses is a maintenance dose) may be replaced.  After the appropriate 
number of initial stage patients in each arm have been enrolled and followed for at 
least 8 weeks, an efficacy and safety analysis will be performed as described in the 
Statistical Analysis Plan (SAP).  The CTSC will convene to review and approve 
proceeding with full accrual of either or both arms, or terminate either arm.  Full 
accrual in either arm may be opened earlier by the CTSC at any point at which 
sufficient anti-cancer activity is observed. The CTSC may also approve further 
enrollment and exploration of additional alternate Phase 2 doses. 
3.4. 
Planned Phase 2 Dose and Schedule 
Based on review of safety, efficacy, and PK data available from Phase 1b, the 
planned and alternate Phase 2 dose and schedule of Hu5F9-G4 that will be used in 
the Phase 2 part of this study and is shown in Table 2. 
When both study drugs are given on the same visit day, Hu5F9-G4 will be 
administered at least 1 hour after the completion of the cetuximab administration. 
Starting with Cycle 2, the Day 8 and Day 22 dosing of Hu5F9-G4 has been removed, 
compared with the Phase 1b schedule (i.e., dosing is Q2W).  Patients enrolled in the 
Phase 1b part of the study who have been on study for at least 8 weeks may have 
their dose revised to the RP2DS, at the discretion of the Investigator. 


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Table 2. 
Phase 2 Dose and Schedule 
Drug/Dose 
(Intravenous) 
Dose Schedule 
(Day per 28-day Cycle) 
Cycle 1 
Cycle 2 
Cycle 3+ 
Current Dose and Schedule 
Hu5F9-G4 1 mg/kg 
(prime) 
Day 1 
— 
—  
Hu5F9-G4 30 mg/kg 
(maintenance) 
Days 8, 15, and 22 
Days 1 and 15  
Days 1 and 15 
Cetuximab 400 mg/m2 
(load) 
Day 8 
— 
— 
Cetuximab 250 mg/m2 
(maintenance) 
Days 15 and 22 
Days 1, 8, 15, and 22 
Days 1, 8, 15, and 22 
Alternate Dose and Schedule 
Hu5F9-G4 1 mg/kg 
(prime) 
Day 1 
— 
—  
Hu5F9-G4 45 mg/kg 
(maintenance) a 
Days 8 ,11, 15, and 22 
Days 1, 8, 15, and 22 
Days 1 and 15 
Cetuximab 400 mg/m2 
(load) 
Day 8 
— 
— 
Cetuximab 250 mg/m2 
(maintenance) 
Days 15 and 22 
Days 1, 8, 15, and 22 
Days 1, 8, 15, and 22 
a 
If recommended by the CTSC, other doses and schedules may be tested in Phase 2 
3.5. 
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 Phase 2 trials, 
including evaluation of multiple Phase 2 doses, and interim efficacy analysis 
decisions.  The CTSC will meet at a minimum at the completion of each dosing 
cohort during dose escalation phase 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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3.6. 
Data Monitoring Committee 
Data Monitoring Committee functions for this trial will be performed by the CTSC, as 
defined and described in Section 3.5. 
3.7. 
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. 
3.8. 
Number of Sites 
Approximately 8 sites located in the US will be included in this trial.  Additional sites 
may be included based on enrollment and study timelines. 
3.9. 
Estimated Study Duration 
It is anticipated that this study will take approximately 42 months to complete. 
Patient participation will include screening, treatment, and follow-up.  Screening will 
last up to 30 days before first dose of study drugs, during which time the patient’s 
eligibility and baseline characteristics will be determined.  Treatment with study 
drugs may be continued until an unacceptable drug-related toxicity occurs, patient 
refusal, or until disease progression.  Post treatment, patients will be observed for 
disease progression and survival until death, withdrawal of consent, or the end of 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 
or patients in Phase 2 who are not evaluable for efficacy as defined in 
Section 11; and patients added to intermediate dose or expanded cohorts as 
determined by the CTSC, and approved, if necessary, by the appropriate IRBs. 


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• The stated objectives of the trial are achieved. 
Interim study database lock may be implemented at the discretion of the CTSC once 
all Phase 2 patients enrolled have achieved at least 1 tumor efficacy assessment. 


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4. SUBJECT SELECTION AND ENROLLMENT 
4.1. 
Inclusion Criteria 
1. Adults ≥ 18 years old. 
2. Histological Diagnosis 
a. Phase 1b only: 
Histologically or cytologically confirmed advanced solid malignancy with 
an emphasis on CRC, head and neck, breast, pancreatic and ovarian 
cancers who have been treated with at least one regimen of prior systemic 
therapy, or who refuse systemic therapy, and for which there is no curative 
therapy available. 
b. Phase 2: 
• KRAS Mutant CRC:  Histologically confirmed advanced KRAS mutant 
CRC who have progressed or are ineligible for fluoropyrimidine, 
irinotecan- and oxaliplatin-based chemotherapy 
OR 
• KRAS Wild-Type CRC:  Histologically confirmed advanced KRAS 
wild-type CRC who have progressed or are ineligible for 
fluoropyrimidine, irinotecan- and oxaliplatin-based chemotherapy and 
who are refractory to at least 1 prior systemic therapy that included an 
anti-EGFR antibody, such as cetuximab, panitumumab, or others.  
Patients should have disease progression during prior anti-EGFR 
therapy or within 6 months of the last day of treatment with the anti-
EGFR. 
3. Eastern Cooperative Oncology Group (ECOG) Score 0-2. 
4. For the Phase 2 part only:  Disease that is measurable or assessable for 
response according to RECIST Version 1.1 Criteria. 
5. Laboratory measurements, blood counts: 
• Hemoglobin ≥ 9.5 g/dL. 
• Absolute neutrophil count (ANC) ≥ 1.0 × 109/mL. 


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• Platelets ≥ 75 × 109/ mL. 
6. Laboratory measurements, hepatic function: 
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) < 5× 
upper limit of normal (ULN). 
• Bilirubin < 1.5X 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. Negative urine or serum pregnancy test within 30 days before administration 
of Hu5F9-G4 for women of childbearing potential. 
9. Females of childbearing potential must be willing to use 1 effective method of 
contraception during the study and continue for 4 months after the last dose 
of Hu5F9-G4 and 6 months after the last dose of cetuximab. 
10. Males must be willing to use 1 effective method of contraception and refrain 
from sperm donation during the study and continue for 4 months after the last 
dose of Hu5F9-G4 and 6 months after the last dose of cetuximab, if the 
partner is a female of childbearing potential. 
11. Subject has provided informed consent. 
12. Must be willing and able to comply with the clinic visits and procedures 
outlined in the study protocol. 
13. Phase 2 only: 
Willing to consent to 1 mandatory pre-treatment and 1 on-treatment tumor 
biopsy, unless determined to not be feasible 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 active brain metastases (patients with stable treated central 
nervous system [CNS] lesions who are off corticosteroid and radiation therapy 
for at least 3 weeks are not considered active). 
2. Prior 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.  Localized non-CNS 
radiotherapy, previous hormonal therapy with luteinizing hormone releasing 
hormone (LHRH) agonists for prostate cancer, low-dose steroids (oral 
prednisone or equivalent ≤ 20 mg per day), and treatment with 
bisphosphonates and RANKL inhibitors are not criteria for exclusion. 
3. Prior treatment with CD47 or SIRPα-targeting agents. 
4. Known active or chronic hepatitis B or C infection or human 
immunodeficiency virus (HIV). 
5. RBC transfusion dependence, defined as requiring more than 2 units of RBC 
transfusions 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. 
6. History of hemolytic anemia or Evans syndrome in the last 3 months. 
7. Phase 2 only: 
Second malignancy, except treated basal cell or localized squamous skin 
carcinomas, localized prostate cancer, or other malignancy for which 
treatment was completed at least 3 years ago and for which there is no 
evidence of recurrence. 
8. Hypersensitivity to the active substance or to murine proteins, or to any of the 
other excipients of cetuximab listed in Appendix A. 
9. Significant medical diseases or conditions, as assessed by the Investigators 
and Sponsor, that would substantially increase the risk-benefit ratio of 
participating in the study.  This includes, but is not limited to, acute myocardial 


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infarction within the last 6 months, unstable angina, uncontrolled diabetes 
mellitus, significant active infections, severely immunocompromised state, 
and congestive heart failure New York Heart Association (NYHA) Class II-IV. 
10. History of psychiatric illness or substance abuse likely to interfere with ability 
to comply with protocol requirements or give informed consent. 
11. Pregnancy or active breast feeding. 
12. 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, receive a unique subject identification 
number before any study procedures are performed.  This number is used to identify 
the patient throughout the clinical trial and must be used on all study documentation 
related to that patient, including if a patient is rescreened. 
Patient Screening laboratory assessments may be tested repeatedly within the 
30 days prior to the first dose of study treatment.  Patients who screen fail may 
undergo repeated screening if the patient’s medical condition has changed. 
All patients who provide informed consent must be registered in the electronic data 
capture (EDC) system, including any screen failures. 
A patient is defined as enrolled in the study once all eligibility criteria have been 
satisfied and the Sponsor or designee has confirmed the cohort or study arm 
assignment.  After signing the informed consent, eligible patients are expected to 
receive the first dose of Hu5F9-G4 (Study 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/Research Ethics 
Committee (IRB/REC) approved informed consent form (ICF) prior to participation in 
any study specific procedure.  Data from assessments performed as part of standard 


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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 subject number at the time of consent.  The site will 
register the patient through interactive web response technology (IWRS) with the 
Sponsor or representative within 2 days of consent. 
Prior to being assigned a dose cohort or treatment arm, patients must have signed 
the informed consent and satisfied all of the eligibility criteria.  Once patients have 
been assigned to a dose cohort or treatment arm, they will be considered enrolled.  
The Investigator will determine the eligibility of the patient. 


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5. STUDY DRUG INFORMATION 
See the Pharmacy Manual for detailed instructions for Hu5F9-G4 and cetuximab 
preparation and handling. 
5.1. 
Hu5F9-G4 
5.1.1. 
Physical Description of Study Drug 
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 
product is a sterile, clear, colorless, preservative-free liquid intended for intravenous 
(IV) infusion. 
Hu5F9-G4 active pharmaceutical ingredient (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. 
5.2. 
Cetuximab 
5.2.1. 
Physical Description of Study Drug 
Erbitux® (cetuximab) is a recombinant, human/mouse chimeric monoclonal antibody 
that binds specifically to the extracellular domain of the human epidermal growth 
factor receptor (EGFR).  Cetuximab is composed of the Fv regions of a mouse 
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and has an approximate molecular weight of 152 kDa.  Cetuximab is produced in 
mammalian (murine myeloma) cell culture. 
Cetuximab is a sterile, clear, colorless liquid of pH 7.0 to 7.4, which may contain a 
small amount of easily visible, white, amorphous cetuximab particulates.  Cetuximab 
is supplied at a concentration of 2 mg/mL as a 100 mg/50 mL single-use vial (NDC 
66733 948 23), or as a 200 mg/100 mL single-use vial (NDC 66733 958 23) as a 
sterile, injectable liquid containing no preservatives individually packaged in a 
carton.  Cetuximab is formulated in a solution containing 8.48 mg/mL sodium 
chloride, 1.88 mg/mL sodium phosphate dibasic heptahydrate, 0.41 mg/mL sodium 
phosphate monobasic monohydrate, and Water for Injection, USP (Appendix A). 
Store vials under refrigeration at 2°C to 8°C (36°F to 46°F) and do not freeze.  
Increased particulate formation may occur at temperatures at or below 0°C.  
Preparations of cetuximab in infusion containers are chemically and physically stable 
for up to 12 hours at 2°C to 8°C (36°F to 46°F) and up to 8 hours at controlled room 
temperature (20°C to 25°C; 68°F to 77°F).  Discard any remaining solution in the 
infusion container after 8 hours at controlled room temperature or after 12 hours at 
2°C to 8°C.  Discard any unused portion of the vial. 


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6. TREATMENT PLAN 
6.1. 
Study Drug Administration Guidance:  Hu5F9-G4 and Cetuximab 
6.1.1. 
Dosing 
Planned Phase 1b dose levels are presented in Table 1 and the Phase 2 dose and 
schedule is presented in Table 2. 
The dose of each study drug will be calculated based on actual weight at enrollment 
(using weight obtained either at Screening or on Day 1) and remains constant 
throughout the study, unless there is a > 10% change in weight from baseline.  
Modifications to the study drug doses administered should be made for a > 10% 
change in body weight and for dose modifications as described in Section 6.1.4.  
Dose modifications for changes in body weight < 10% may be made according to 
local institutional guidelines. 
All patients will receive an Hu5F9-G4 priming dose of 1 mg/kg on Day 1.  
The duration of the infusion of the priming dose will be 3 hours (± 30 minutes).  
The priming dose will be followed by a weekly maintenance dose.  The duration of 
the infusion of the maintenance dose will be 2 hours (± 30 minutes).  The first 
maintenance dose will be administered starting on Day 8 after the completion of the 
first dose of cetuximab.  All subsequent maintenance doses of Hu5F9-G4 will be 
administered at the start of each study week (± 1 day).  Hu5F9-G4 will be 
administered at least 1 hour after the completion of cetuximab administration. 
All patients should be monitored for at least 1 hour post-infusion for the first 4 weeks.  
Post-infusion monitoring should begin after the last study drug is given.  
Post-infusion monitoring is not required for doses after Cycle 1.  Patients who 
experience any treatment-related AEs during the observation period should be 
further monitored, as clinically appropriate. 
Patients will receive a cetuximab dose of 300-400 mg/m2 given IV starting on Day 8, 
followed by weekly dosing at 200-250 mg/m2 on Days 15 and 22.  Starting at 


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Cycle 2, and for each cycle thereafter, cetuximab will be given weekly starting on 
Day 1.  (Details are provided in Section 6.1.4.2.) 
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 iRECIST (Seymour 2017) may not be indicative of 
true PD.  Hu5F9-G4 and cetuximab combination treatment may continue past the 
initial determination of disease progression according to iRECIST 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 
• Treatment beyond progression will not delay an imminent intervention to prevent 
serious complications of disease progression (for example, central nervous 
system [CNS] metastases) 
6.1.2. 
Premedication 
Premedication is required before administration of the first cetuximab dose and 
before the first 2 doses of Hu5F9-G4 (inclusive of the priming dose).  At the 
discretion of the Investigator, administration of premedication may continue for 
subsequent doses of cetuximab and/or Hu5F9-G4.  
Hu5F9-G4 
Premedication with oral acetaminophen 650 to 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.  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 


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infusion-related reactions.  Premedications used to manage infusion-related 
reactions are described in Sections 6.1.4.2.2 and 6.1.5.2.4. 
Cetuximab 
From 30 to 60 minutes prior to administration of the first dose of cetuximab, patients 
should be premedicated with an H1 antagonist (e.g., 50 mg of diphenhydramine) 
intravenously.  Continued use of premedications plus the addition of other agents 
(i.e., glucocorticoids, etc.) should be implemented as required by local standards of 
practice and at the discretion of the Investigator. 
6.1.3. 
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 Q2W dosing schedule. 
• Patients who experience an interruption of >4 weeks after receiving at least 
1 maintenance dose (i.e., 30 mg/kg) must be “reprimed” by receiving the 
Hu5F9-G4 priming dose of 1 mg/kg IV over 3 hours (±30 minutes) and 
3 weekly maintenance doses prior to starting the Q2W schedule. 
• Cetuximab must be administered as regularly scheduled (e.g. Hu5F9-G4 
repriming doses may be administered on the same day as cetuximab is given 
and administration of cetuximab once weekly 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): 
• Complete blood count (CBC) with differential, platelets, reticulocytes 


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• Peripheral blood smear 
• Serum chemistry 
• Haptoglobin, D-dimer, thrombin, fibrinogen 
• PT/INR, aPTT 
• Vital signs 
• Physical examination 
• Adverse events 
• Concomitant medications 
 
6.1.4. 
Dose Delays, Dose Modifications, and Safety Management 
Guidelines 
6.1.4.1. 
Hu5F9-G4 
Dose modification or dose delay of Hu5F9-G4 may not occur for patients in the initial 
28-day DLT assessment period in the Phase 1b part of the study or for patients in 
the first cycle of the Phase 2 part of the study.  After the initial 28-day treatment 
period for evaluation of DLTs, Hu5F9-G4 may be withheld if treatment-emergent 
Hu5F9-G4-related AEs occur, which include all AEs that constitute a DLT as defined 
in Section 3.2.4.  If the severity has recovered to Grade 0 to 2 within 4 weeks and in 
the absence of disease progression, Hu5F9-G4 may be re-introduced at the next 
lower dose level.  Patients who experience a DLT of either hemolytic anemia or 
Grade ≥ 4 non-hematological toxicity will not restart Hu5F9-G4 and will be withdrawn 
from study drug treatment.  Restarting treatment after a delay of more than 4 weeks 
(such as for an unrelated medical condition with expected recovery) must be 
approved by the medical monitor. 
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) 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 repriming dose prior to resuming the Q2W dosing 
schedule (Section 6.1.3, Repriming). 


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6.1.4.1.1. 
Interruption of Hu5F9-G4 Treatment 
For patients who experience dose interruptions, instructions for repriming are 
provided in Section 6.1.3. 
6.1.4.1.2. 
Maintenance Dose Schedule Modification 
Patients who have completed at least 8 weeks of weekly maintenance therapy may 
stay at the same infusion dose, but may have their Hu5F9-G4 schedule of 
administration extended to every 2 or 3 weeks, if supported by PK data and 
approved by the CTSC. 
6.1.4.1.3. 
Intra-patient Dose Escalation 
In the Phase 1b part of the study, patients who have been on study for at least 
8 weeks may have their maintenance dose escalated to a higher dose level that has 
been previously demonstrated to be safe in this study, at the discretion of the 
Investigator and the CTSC. 
6.1.4.2. 
Cetuximab 
6.1.4.2.1. 
Administration 
Cetuximab should not be given as an intravenous push or bolus; instead, it should 
be administered by infusion pump or syringe pump at an infusion rate that should not 
exceed 10 mg/min.  It should also be administered through a low protein binding 
0.22-micrometer in-line filter.  The parenteral drug product should be inspected 
visually for particulate matter and discoloration prior to administration, whenever 
solution and container permit.  The solution should be clear and colorless and may 
contain a small amount of easily visible, white, amorphous, cetuximab particulates.  
Do not shake or dilute the solution. 
6.1.4.2.2. 
Infusion Reactions 
Serious infusion reactions requiring medical intervention and immediate, permanent 
discontinuation of cetuximab included rapid onset of airway obstruction 
(bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, 


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myocardial infarction, and/or cardiac arrest.  Severe (NCI CTCAE Grades 3 and 4) 
infusion reactions occurred in 8.4% of 1373 patients receiving cetuximab in 4 
different clinical studies, with a fatal outcome in 1 patient (Cetuximab [Erbitux®] 
Prescribing Information, Appendix A).  Approximately 90% of severe infusion 
reactions occurred with the first infusion despite premedication with antihistamines. 
Patients should be monitored for 1 hour following cetuximab infusion in a setting with 
resuscitation equipment and other agents necessary to treat anaphylaxis 
(e.g., epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and 
oxygen).  If serious infusion reactions occur, study drug administration should be 
immediately interrupted and permanently discontinued.  If hypersensitivity or 
infusion-related events develop, the infusion rate should be reduced by 50% for NCI 
CTCAE Grade 1 or 2 and non-serious NCI CTCAE Grade 3 infusion reactions.  
Patients who experience infusion reactions must be observed until resolution of the 
event. 
6.1.4.2.3. 
Cardiopulmonary Arrest 
Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients 
treated with radiation therapy and cetuximab as compared to none of 212 patients 
treated with radiation therapy alone (Cetuximab [Erbitux®] Prescribing Information, 
Appendix A).  Carefully consider the use of cetuximab in combination with radiation 
therapy or platinum-based therapy with 5-FU in head and neck cancer patients who 
have a history of coronary artery disease, congestive heart failure, or arrhythmias in 
light of these risks.  Closely monitor serum electrolytes, including serum magnesium, 
potassium, and calcium, during and after cetuximab infusion. 
6.1.4.2.4. 
Pulmonary Toxicity 
Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (< 0.5%) 
patients receiving cetuximab in 3 clinical trials (Cetuximab [Erbitux®] Prescribing 
Information, Appendix A), as well as in other studies in colorectal cancer and head 
and neck cancer.  Monitor patients for signs and symptoms of pulmonary toxicity and 


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interrupt cetuximab for acute onset or worsening of pulmonary symptoms and 
permanently discontinue cetuximab for confirmed ILD. 
6.1.4.2.5. 
Dermatologic Toxicity 
Dermatologic toxicities, including acneiform rash, skin drying and fissuring, 
paronychial inflammation, infectious sequelae (for example, S. aureus sepsis, 
abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis 
with decreased visual acuity, cheilitis), and hypertrichosis occurred in patients 
receiving cetuximab therapy.  Acneiform rash occurred in 82% of 1373 patients 
receiving cetuximab in 4 clinical trials (Cetuximab [Erbitux®] Prescribing Information, 
Appendix A).  Severe acneiform rash occurred in 9.7% of patients. 
Acneiform rash usually developed within the first 2 weeks of therapy and resolved in 
a majority of the patients after cessation of treatment, although in nearly half, the 
event continued beyond 28 days.  Life-threatening and fatal bullous mucocutaneous 
disease with blisters, erosions, and skin sloughing has also been observed in 
patients treated with cetuximab.  It could not be determined whether these 
mucocutaneous adverse reactions were directly related to EGFR inhibition or to 
idiosyncratic immune-related effects (e.g., Stevens-Johnson syndrome or toxic 
epidermal necrolysis).  Prophylactic interventions for cetuximab skin rash using oral 
and/or topical antibiotics, sun block, moisturizing creams, or other agents may be 
instituted according to local standard of care.  Possible oral antibiotic regimens for 
skin prophylaxis include oral doxycycline 100 mg twice-weekly or comparable 
regimens with tetracycline or minocycline.  Patients will be monitored for 
dermatologic toxicities and infectious sequelae and they will be instructed to limit sun 
exposure during cetuximab therapy. 
Recommended dose modifications for severe (NCI CTCAE Grade 3 or 4) acneiform 
rash are specified in Table 3. 


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Table 3. 
Cetuximab Dose Modification Guidelines for Rash 
Severe 
Acneiform Rash 
Cetuximab 
Outcome 
Cetuximab 
Dose Modification 
First occurrence 
Delay infusion 1 
to 2 weeks 
Improvement 
Continue at 250 mg/m2 
No Improvement 
Discontinue cetuximab 
Second occurrence 
Delay infusion 1 
to 2 weeks 
Improvement 
Continue at 200 mg/m2 
No Improvement 
Discontinue cetuximab 
Third occurrence 
Delay infusion 1 
to 2 weeks 
Improvement 
Continue at 150 mg/m2 
No Improvement 
Discontinue cetuximab 
Fourth occurrence 
Discontinue 
cetuximab 
 
 
Source:  Cetuximab (Erbitux®) Prescribing Information (Appendix A). 
 
6.1.4.2.6. 
Hypomagnesemia and Electrolyte Abnormalities 
In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of 365 
patients receiving cetuximab in one trial (Appendix A) and it was severe (NCI 
CTCAE Grades 3 and 4) in 6%–17%.  In one study in which cetuximab was 
administered in combination with platinum-based therapy, the addition of cetuximab 
to cisplatin and 5-FU resulted in an increased incidence of hypomagnesemia (14% 
vs. 6%) and of Grade 3–4 hypomagnesemia (7% vs. 2%) compared to cisplatin and 
5-FU alone.  In contrast, the incidences of hypomagnesemia were similar for those 
who received cetuximab, carboplatin, and 5-FU compared to carboplatin and 5-FU 
(4% vs. 4%).  No patient experienced Grade 3–4 hypomagnesemia in either arm in 
the carboplatin subgroup.  The onset of hypomagnesemia and accompanying 
electrolyte abnormalities occurred days to months after initiation of cetuximab.  
Periodically monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia, 
during and for at least 8 weeks following the completion of cetuximab. 
6.1.5. 
Specific Safety Management Guidelines 
6.1.5.1. 
Cetuximab 
Safety management guidelines for cetuximab are provided in (Cetuximab [Erbitux®] 
Prescribing Information, Appendix A). 


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6.1.5.2. 
Hu5F9-G4 
6.1.5.2.1. 
Hemagglutination and Microangiopathy 
In the Phase 1 trial experience with Hu5F9-G4 in solid tumors and acute myeloid 
leukemia, agglutination of RBCs has been observed on peripheral smear.  
Hu5F9-G4-related microangiopathy is a possible sequela of hemagglutination.  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 (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  
PPD


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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 
 
6.1.5.2.2. 
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 
a possibility that treatment with Hu5F9-G4 may obscure assessment of red blood 
cell 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 7.3.4.  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 PI, perform the 
following procedures:  
• Front Type:  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 


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(LISS), repeat the antibody screen with polyethylene glycol (PeG).  Perform 
PeG adsorption studies and elution studies. 
6.1.5.2.3. 
Blood Components for Transfusion 
For all elective red cell transfusions, leucocyte-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. 
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. 
6.1.5.2.4. 
Management of Hu5F9-G4 Infusion 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 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. 


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• 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 treat 
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 60 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. 
o No further Hu5F9-G4 will be administered at that visit. 
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 reaction during the post-infusion 
observation period that does not resolve during that time should be observed 
until the AE resolves or stabilizes, with vital sign measurements every 4 hours 
and additional evaluations 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 signs and symptoms (e.g., not rapidly responsive to symptomatic 
medication and/or brief interruption of infusion), or recurrence of symptoms 


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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 treat 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 reactions occurring with the first dose will 
be permanently discontinued from study treatment. 
o Patients who experience Grade 3 infusion reactions must be given 
premedication prior subsequent doses.  In this setting, premedication with 
oral acetaminophen (650 mg), oral or intravenous diphenhydramine 
(25-50 mg), and intravenous dexamethasone (4-20 mg), or a comparable 
regimen, is recommended. 
o Patients who receive premedication and still have a Grade 3 or 4 infusion 
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). 
6.1.5.2.5. 
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 


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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. 
6.2. 
Post-therapy Follow-up and Patient Study Completion 
Patients who complete, terminate, or decline further treatment should be 
encouraged to return for an End of Treatment Visit for evaluation of safety within 
1 week of the decision to end Hu5F9-G4 treatment.  The studies to be performed at 
end of treatment are listed in the Schedules of Assessments (SOAs), Section 7.4.  It 
is strongly encouraged that patients return for their Safety Follow-up Visit 30 days 
(± 1 week) after the last dose of last study drug received.  The Safety Follow-up Visit 
assessments are described in Section 7.5. 
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 the last study 
drug received, unless they are experiencing ongoing drug-related AEs and serious 
adverse events (SAEs).  For patients being followed for ongoing AEs or SAEs, 
follow-up visits will continue at least every 4 weeks until resolution to baseline or 
stabilization of these events, unless the patient starts another anti-cancer therapy.  
Follow-up for ongoing AEs or SAEs after the Safety Follow-up Visit will stop if a 
patient begins another anti-cancer therapy. 
All patients, including those who discontinue study treatment early, will be followed 
for response until progression and for survival for 5 years from the date of 
enrollment.  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. 


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6.3. 
Defining the End of Trial 
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 follow-up for safety, disease 
progression, or survival, or when the CTSC decides to end the study. 
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. 
In terminating the trial, the Sponsor and the Investigators must ensure that adequate 
consideration is given to the protection of the patient’s interest. 


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7. STUDY EVALUATIONS 
7.1. 
Schedules of Assessment for Phase 1b and Phase 2 
Table 4 presents the SOA for the Phase 1b part of the study.  The SOA for the 
Phase 2 part of the study is provided in Table 5.  Unless otherwise noted procedures 
are to be completed prior to any study drug infusion.  Table 6 shows post-treatment 
assessments for both phases of the study.  Table 7 and Table 8 describes PK 
assessments for Phases 1b and 2, respectively.  Table 9 describes the timing of 
correlative study sample collection and Table 10 provides details for CD47 receptor 
occupancy sampling for Phase 1b. 
 


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Table 4. 
Schedule of Assessments Phase 1 b 
Examination 
Study 5F9004, Phase 1 b: Phase 1b/2 Solid Tumor/CRC Patient Trial with Hu5F9-G4 + Cetuximab 
Cycle (28-day 
1 
2 
3 
4 
5+ 
cycles) 
Cycle Day 
SC 
1 
2 
8 
9 
11 
15 
22 
1 
2 
4 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
Visit Window 
-30 
None 
±1 
±2 
±1 
± 2 
(Days) 
Assessments 
Informed consent 
X 
Demographics 
X 
Medical and 
X 
cancer history 
Inclusion/exclusion 
X 
criteria 
Enrollment cohort 
X 
assignmenta 
Serum or Urine 
X 
X 
::la 
Pregnancy Test 
w 
CBC with 
differential, 
X 
X X X 
X 
X 
X 
X X 
X 
X X 
X 
X 
X X 
X 
X 
X 
X 
platelets, 
reticulocytesc 
Peripheral Blood 
Smear' 
X 
')( X X 
X 
X 
X 
X 
Serum chemistryc 
X 
X X X 
X 
X 
X 
X X 
X 
X X 
X 
X 
X X 
X 
X 
X 
X 
Serum uric acid, 
X 
X X X 
X 
phosphorousc 
Forty Seven Inc. 
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Hu5F9-G4 
Protocol 5F9004, Amendment 3 
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Examination 
Study 5F9004, Phase 1 b: Phase 1b/2 Solid Tumor/CRC Patient Trial with Hu5F9-G4 + Cetuximab 
Cycle (28-day 
1 
2 
3 
4 
5+ 
cycles) 
Cycle Day 
SC 
1 
2 
8 
9 
11 
15 
22 
1 
2 
4 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
Visit Window 
-30 
None 
±1 
±2 
±1 
±2 
(Days) 
Assessments 
Haptog lobin, 
D-Dimer, thrombin 
X 
X X X 
X 
X 
X 
X 
X 
X 
time, and plasma 
fibrinogenc 
PT/INR, aPTrt 
X 
X 
X 
X 
X 
X 
Type and Screen 
X 
(ABO/Rh), DA TP 
Urinalysisc 
X 
X 
Correlative 
X 
X 
X 
X 
xi 
studiese 
Pharmacokineticsr 
X 
X X 
X 
X 
X 
X X X X X 
X 
X X 
X 
';( 
Antidrug 
X 
X 
X 
X 
X 
X 
Antibodies 
CD4 7 Receptor 
X X X 
x 
X 
X 
X 
X 
X 
X 
xi 
Occupancy9 
ECOG 
performance 
X 
X 
X 
X 
X 
X 
X 
X 
X 
status 
Vital signsh 
X 
X X X 
x 
X 
X 
X 
X X 
X 
X X 
X 
X 
X X 
X 
X 
X X 
X 
X 
Physical 
X 
)(; 
X 
X 
X 
X 
X 
X 
X 
X 
X 
examinationi 
DL T Assessmenti 
X 
Visual acuity 
X 
)(; 
X 
X 
X 
X 
X 
X 
X 
Forty Seven Inc. 
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Hu5F9-G4 
Protocol 5F9004, Amendment 3 
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Examination 
Study 5F9004, Phase 1 b: Phase 1b/2 Solid Tumor/CRC Patient Trial with Hu5F9-G4 + Cetuximab 
Cycle (28-day 
1 
2 
3 
4 
5+ 
cycles) 
Cycle Day 
SC 
1 
2 
8 
9 
11 
15 
22 
1 
2 
4 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
Visit Window 
-30 
None 
±1 
±2 
±1 
± 2 
(Days) 
Assessments 
ECGk 
X 
X 
X 
X 
PPD 
Response 
x 
X" 
QB 
assessment 
W1 
Adverse events 
,_ 
,~ 
Concomitant 
medications 
,~ 
Study Drug 
Administration 
Cetuximab 
X' 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X X 
X 
X 
X X 
X 
Hu5F9-G4 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X X 
X 
X 
X X 
X 
(Cohorts 1-4) 
Hu5F9-G4 
X 
x 
x 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(Cohort 5 ) 
Abbreviations: ABO = any of the four blood groups A, B, AB, and O comprising the ABO system; aPTT = activated partial thromboplastin time; C 
= cycle number; CBC = complete blood count; DAT = direct antiglobulin test; DL T = dose-limiting toxicity; ECG = electrocardiogram; ECOG = 
Eastern Cooperative Oncology Group; INR = international normalized ratio; PT = prothrombin time; Rh = Rhesus factor; RO= CD47 receptor 
occupancy; SC = Screening; W = weeks. 
a. First dose of Hu5F9-G4 must be given within 30 days of all Screening tests. 
Forty Seven Inc. 
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X 
X 


Hu5F9-G4 
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Examination 
Study 5F9004, Phase 1 b: Phase 1b/2 Solid Tumor/CRC Patient Trial with Hu5F9-G4 + Cetuximab 
Cycle (28-day 
1 
2 
3 
4 
5+ 
cycles) 
Cycle Day 
SC 
1 
2 
8 
9 
11 
15 
22 
1 
2 
4 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
Visit Window 
-30 
None 
±1 
±2 
±1 
± 2 
(Days) 
Assessments 
b. May use Screening pregnancy test performed within 72 hours of first dose. 
c. Pre-infusion assessments may be performed up to 72 hours before study drug treatment. 
d. Peripheral blood smear slides from Cycle 1 will be retained and sent to the Sponsor for storage. Collection details are provided in 
Section 7.3.5. 
e. Refer to Table 9 for correlative studies timepoint details. 
f. 
Refer to Table 7 for PK timepoint details. 
g. Refer to Table 10 for RO timepoint details. 
h. Prior to infusion and within 30 minutes after each infusion (if applicable). Details about data to be collected are provided in Section 7.3.2. 
i. 
Full physical examination at Screening, symptom-directed PE thereafter. 
j. 
DL T will be assessed through the first 4 weeks of the study. 
k. Single at Screening. Triplicate within 2 hours prior to cetuximab infusion and within 30 minutes of the end of Hu5F9-G4 infusion on treatment 
for Phase 1 b only. 
I. 
Loading Dose Cohort only: Doses of Hu5F9-G4 administered on Day 8 and 11 may be shifted by ± 1 day, provided that doses are not 
administered on consecutive days. 
m. (± 1 week) Efficacy assessment details are provided in Section 7.9. 
n. After Cycle 3, the adjustment window is ± 2 weeks. 
o. From 30 to 60 minutes prior to administration of the first dose of cetuximab, patients should be premedicated with an H1 antagonist (e.g., 
50 mg of diphenhydramine) intravenously. 
p. Detailed guidance is provided in Section 7.3.4. 
q. To be performed with response assessment (± 1 week from Cycle 3, Day 1). 
r. 
Starting with Cycle 5, samples to be collected every other cycle (e.g~
_cl_e_5_,_,_7.,_, 9--', .... a_n_d_s_o_o_n.,) .. ______________ _ 
s. PPD 
22 
t. 
R1stonc imaging may be used for screening d1agnos Ic imaging if performed within 30 days of the first dose of Hu5F9-G4; details are provided 
in Section 10. 
u. Archival tumor tissue may be collected by the sponsor for correlative studies. The tissue block is preferred, but if not available at least 
10 unstained slides are suggested. 
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Table 5. 
Schedule of Assessments Phase 2 
Examination 
Study 5F9004, Phase 2: P1 b/2 Solid Tumor/CRC Trial of Hu5F9-G4 + Cetuximab 
Cycle (28-day cycles) 
1 
2 
3 
4 
5+ 
Cycle Day 
SC 
1 
2 
8 
9 
11 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
Visit Window (Days) 
-30 
None 
±1 
±2 
±1 
± 2 
Assessments 
Informed Consent 
X 
Demographics 
X 
Medical and Cancer 
X 
History 
Inclusion/Exclusion 
X 
Criteria 
Enrollment Cohort 
X 
assignmenta 
Serum or Urine Pregnancy 
X 
X' 
X 
Q8 
Test 
w 
CBC w differential, 
X 
X X X 
X 
X 
X X 
X 
X 
X X 
X 
X 
X X 
X 
X 
X 
X 
platelets, reticulocytesc 
Peripheral Blood Smeard 
X 
)( X X 
X 
X 
X 
X 
Serum chemistryc 
X 
X X X 
X 
X 
X X 
X 
X 
X X 
X 
X 
X X 
X 
X 
X 
X 
Serum uric acid, 
X 
X X X 
X 
phosphorousc 
Haptoglobin, D-Dimer, 
thrombin time, and plasma 
X 
X X X 
X 
X 
X 
X 
X 
X 
fibrinogenc 
PT/INR, aPTrc 
X 
X 
X 
X 
X 
X 
Type and Screen 
Xf' 
(ABO/Rh), DAT 
Forty Seven Inc. 
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Hu5F9-G4 
Protocol 5F9004, Amendment 3 
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Examination 
Study 5F9004, Phase 2: P1 b/2 Solid Tumor/CRC Trial of Hu5F9-G4 + Cetuximab 
Cycle (28-day cycles) 
1 
2 
3 
4 
5+ 
Cycle Day 
SC 
1 
2 
8 
9 
11 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
Visit Window (Days) 
-30 
None 
±1 
±2 
±1 
± 2 
Assessments 
Urinalysisc 
X 
X 
Correlative studiese 
X 
X 
X 
q 
Pharmacokineticst 
X 
X 
X 
X X 
X 
X 
X 
X 
Antidrug Antibodies 
X 
X 
X 
X 
X 
X 
CD47 Receptor Occupancy9 
ECOG performance status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signsh 
X 
X X X 
x 
X 
X 
X X 
X 
X 
X X 
X 
X 
X X 
X 
X 
X X 
X 
X 
Physical examination; 
X 
')( 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Visual acuity 
X 
')( 
X 
X 
X 
X 
X 
X 
X 
ECGk 
X 
~PD 
Response assessment 
')f 
X" 
Adverse events 
Concomitant medications 
Study Drug Administration 
Cetuximab administration 
)f 
X 
X 
X X 
X 
X 
X X 
X 
X 
X X 
X 
X 
X X 
X 
X 
Hu5F9-G4 administration• 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Examination 
Study 5F9004, Phase 2: P1 b/2 Solid Tumor/CRC Trial of Hu5F9-G4 + Cetuximab 
Cycle (28-day cycles) 
1 
2 
3 
4 
5+ 
Cycle Day 
SC 
1 
2 
8 
9 
11 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
Visit Window (Days) 
-30 
None 
±1 
±2 
±1 
± 2 
Assessments 
Abbreviations: ABO = any of the four blood groups A, B, AB, and O comprising the ABO system; aPTT = activated partial thromboplastin time; 
C = cycle number; CBC= complete blood count; DAT= direct antiglobulin test; DLT = dose-limiting toxicity; ECG = electrocardiogram; 
ECOG = Eastern Cooperative Oncology Group; INR = international normalized ratio; PT = prothrombin time; Rh = Rhesus factor; SC= 
Screening; W = weeks. 
a. First dose of Hu5F9-G4 must be given within 30 days of all Screening tests. 
b. May use Screening pregnancy test performed within 72 hours of first dose. 
c. Pre infusion assessments may be performed up to 72 hours before study drug treatment. 
d. Peripheral blood smear slides from Cycle 1 will be retained and sent to the Sponsor for storage. Details are provided in Section 7.3.5. 
e. Refer to Table 9 for Correlative studies timepoint details. 
f. Refer to Table 8 for PK timepoint details. 
g. Beginning with Protocol Amendment 3, samples for receptor occupancy will not be collected in the Phase 2 part of the study. 
h. Prior to infusion and within 30 minutes after each infusion (if applicable). Details are provided in Section 7.3.2. 
i. Full physical examination at Screening, symptom directed PE thereafter. 
j . This is a placeholder from Phase 1; this footnote does not appear in the Phase 2 SOA. 
k. Single at Screening. Triplicate within 2 hours prior to infusion and within 30 minutes of the end of infusion on treatment for Phase 1 b only. 
I. Loading Dose Cohort only: Doses of Hu5F9-G4 administered on Day 8 and 11 , may be shifted by ± 1 day, provided that doses are not 
administered on consecutive days. 
m. (± 1 week) Efficacy assessment details are provided in Section 7.9. 
n. After Cycle 3, the adjustment window is ± 2 weeks. 
o. From 30 to 60 minutes prior to administration of the first dose of cetuximab, patients should be premedicated with an H1 antagonist (e.g., 
50 mg of diphenhydramine) intravenously. 
p. Detailed guidance is provided in Section 7 .3.4. 
q. To be performed with response assessment (± 1 week from Cycle 3, Day 1 ). 
r. 
PD 
s. Ristoncimaging may be used'tor screening cfiagnostic imaging if performed within 30 days of the first dose of Hu5F9-G4; details are provided 
in Section 10. 
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Examination 
Study 5F9004, Phase 2: P1 b/2 Solid Tumor/CRC Trial of Hu5F9-G4 + Cetuximab 
Cycle (28-day cycles) 
1 
2 
3 
4 
5+ 
Cycle Day 
SC 
1 
2 
8 
9 
11 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
Visit Window (Days) 
-30 
None 
±1 
±2 
±1 
± 2 
Assessments 
.. 
t 
Per CTSC, alternate Phase 2 doses and schedules may include add1t1onal Hu5F9-G4 dosing time points. 
u. Archival tumor tissue may be collected by the sponsor for correlative studies. The tissue block is preferred, but if not available at least 
10 unstained slides are suggested. 
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Table 6. 
Post-treatment Assessments, Phase 1b and Phase 2 
Examination 
Study 5F9004, Post-treatment Assessments: 
Phase 1b/2 Solid Tumor/CRC Trial of Hu5F9-G4 + 
Cetuximab 
Cycle (28-day cycles) 
End of 
Treatment 
Safety 
Follow-up 
Long-term 
Follow-up 
Survival 
Follow-up 
 
Within 
1 Week of 
EOT 
Decision 
30 Days 
after Last 
Dose of 
study drug 
Until disease 
progression 
or new 
anti-cancer 
therapy 
Up to 
60 months 
from date of 
LPE 
Visit Window  
 
± 1 Week 
± 2 Weeks 
± 1 Month 
Assessments 
 
 
 
 
Serum or urine pregnancy test 
 
X 
 
 
CBC w differential, platelets, 
reticulocyte count 
 
X 
 
 
Peripheral blood smear 
 
X 
 
 
Serum chemistry 
 
X 
 
 
Haptoglobin, D-Dimer, thrombin 
time, and plasma fibrinogen 
 
X 
 
 
PT/INR, aPTT 
 
X 
 
 
Pharmacokinetics 
Xa 
Xa 
 
 
Correlative studies 
X 
 
Xb 
 
Antidrug Antibodies 
X 
X 
 
 
CD47 Receptor Occupancy 
Xc 
 
 
 
ECOG performance status 
 
X 
 
 
Vital signs 
 
X 
 
 
Physical examination 
(symptom directed) 
 
X 
 
 
Response assessment 
Xe 
Xd,e 
Q8Wb 
 
Adverse events 
X 
X 
Q4Wb 
 
Concomitant medications 
X 
X 
 
 
Survival follow-up and new 
anti-cancer therapy 
 
 
 
Q3M 
Abbreviations:  aPTT = activated partial thromboplastin time; CBC = complete blood count; 
CRC = colorectal cancer; DLT = dose-limiting toxicity; ECOG = Eastern Cooperative Oncology 
Group; EOT = End of Treatment Visit; INR = international normalized ratio; LPE = last patient 
enrolled; M = month(s); PT = prothrombin time’ W = week(s). 
a. Required only in Phase 1b. 
b. Details provided in Section 7.6. 
c. Sample to be collected only if the visit occurs prior to Cycle 2. Samples are collected only for 
Phase 1b, Cohorts 1 to 4. 
d. Required only if not completed within the 4 weeks prior to the Safety Follow-up Visit. 
e. Details provided in Section 10. 
 
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Table 7. 
Pharmacokinetic Assessments, Phase 1b 
Phase 1b 
Cycle 1 
Cycle 2 
Cycle 3 
C4-C5 
C7+ 
EOT 
SFU 
Day 
1 
8 
9 
11 
15 
22 
1 
2 
4 
8 
15 
22 
1 
8 
1 
1 
— 
— 
Before cetuximab infusion 
(within 12 hr) 
 
X 
 
 
X 
X 
X 
 
 
 
 
 
X 
X 
Xa 
 
X 
X 
Before Hu5F9-G4 infusion 
(within 12 hr)  
X 
Xb 
 
 
Xb 
Xb 
Xb 
 
 
Xb 
Xb 
Xb 
Xb 
Xb 
Xa,b 
Xa 
X 
X 
1 hr (± 15 min) 
after Hu5F9-G4 infusion 
X 
X 
 
 
X 
X 
X 
 
 
X 
 
 
X 
X 
Xa 
Xa 
 
 
24 hr (± 8 hr) after 
Hu5F9-G4 infusion (Cycle 1 
Day 8 or Cycle 2 Day 1) 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
72 hr (± 12 hr) after 
Hu5F9-G4 infusion (Cycle 1 
Day 8 or Cycle 2 Day 1) 
 
 
 
Xc 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
1 hr (± 15 min) after 
cetuximab infusion 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
Xa 
 
 
 
Abbreviations:  C = cycle; EOT = End of Treatment Visit; hr = hour(s); min = minute(s); SFU = Safety Follow-up Visit. 
a 
Starting with Cycle 5, samples to be collected every other cycle (e.g., Cycle 5, 7, 9, and so on). 
b. Hu5F9-G4 sample may be collected before the cetuximab infusion at same time as “pre-cetuximab infusion” PK timepoint. 
c 
Sample to be collected before Hu5F9-G4 dose when applicable to Loading Dose Cohort. 
 
 


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Table 8. 
Pharmacokinetic Assessments, Phase 2 
Phase 2 
Cycle 1 
Cycle 2 
C3 
C4 
C5+ 
Day 
1 
8 
15 
1 
8 
15 
1 
1 
1 
Before cetuximab 
infusion (within 12 hr) 
 
X 
 
X 
 
X 
X 
X 
Xa 
1 hr (±15 min) after 
cetuximab infusion 
 
X 
X 
X 
 
 
X 
X 
Xa 
Before Hu5F9-G4 
infusion (within 12 hr) 
X 
Xb 
Xb 
Xb 
 
X 
Xb 
Xb 
Xa,b 
1 hr (±15 min) after 
Hu5F9-G4 infusion 
X 
X 
X 
X 
 
X 
X 
X 
Xa 
Abbreviations:  C = cycle; hr = hour(s); min = minute(s). 
Note:  If at any point in the study the CTSC determines that sufficient PK data have been 
generated, it may halt the collection of PK samples. 
a. Starting with Cycle 5, samples to be collected every fourth cycle (e.g., Cycle 5, 9, 13, end of 
treatment, and survival follow-up). 
b. Hu5F9-G4 sample may be collected before the cetuximab infusion at same time as “pre-
cetuximab infusion” PK timepoint. 
 
Table 9. 
Correlative Studies Sample Time Points, Phases 1b and 2 
Time Points 
Cycle 1 
Cycle 
2 
Cycle 
3 
EOT 
LTFU 
Day 
1 
8 
15 
1 
1 
 
 
Phase 1b 
 
 
 
 
 
 
 
Pre-study drug infusion a,b 
X 
X 
X 
X 
Xc 
 
 
1 hour (± 15 min) after 
Hu5F9-G4 infusion 
X 
X 
X 
 
 
 
 
Phase 2 
 
 
 
 
 
 
 
Pre-study drug infusion a,b 
X 
 
 
X 
Xc 
 
 
1 hour (±15 min) after 
Hu5F9-G4 infusion 
X 
 
 
 
 
 
 
Phase 1b and Phase 2 
 
 
 
 
 
Xd 
Xe 
Abbreviations:  EOT = End of Treatment Visit; LTFU = long-term follow-up; min = minute(s). 
a. Sample to be collected before cetuximab infusion when applicable. 
b. Pre-infusion laboratory tests may be collected up to 72 hours before study drug treatment. 
c. To be performed with response assessment (± 1 week from Cycle 3, Day 1). 
d. Sample to be collected within 1 week of EOT decision. 
e. Obtained at the time of disease progression, or the start of a new anti-cancer therapy. 
 


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Table 10. 
CD47 Receptor Occupancy Sample Time Points, Phase 1b, 
Cohorts 1 to 4 
Time Points 
Cycle 1 
Cycle 2 
C3 
C4+ 
EOT 
Day 
1 
2 
8 
11 
15 
22 
1 
8 
1 
1 
— 
Pre-study drug 
infusion 
X 
 
Xa 
Xb 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa,c 
Xd 
1 hr (± 15 min) 
after Hu5F9-G4 
infusion 
X 
 
X 
Xb 
X 
X 
 
 
X 
Xc 
 
24 hr (± 8 hr) after 
Hu5F9-G4 infusion 
on Day 1 
 
X 
 
 
 
 
 
 
 
 
 
72 hour (± 8 hr) 
after Hu5F9-G4 
infusion on Day 8e 
 
 
 
X 
 
 
 
 
 
 
 
Abbreviations:  C = cycle; EOT = End of Treatment Visit; hr = hour(s); min = minute(s). 
a. 
Sample to be collected before cetuximab infusion when applicable. 
b. 
Samples to be collected from patients in the loading dose cohort only. 
c. 
Starting with Cycle 5, samples to be collected every other cycle (e.g., Cycles 5, 7, 9, and so 
on). 
d. 
Sample to be collected only if the visit occurs prior to Cycle 2. 
e 
Sample to be collected from patients in non-loading dose cohort(s) only. 
 


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7.2. 
Assessment by Study Period 
7.2.1. 
Screening Assessments 
The following procedures are to be completed during the Screening period:   
• Confirmation that the Informed Consent Form has been signed and consent 
process has been documented. 
• Confirmation that all inclusion/exclusion criteria have been met. 
• Demographic data including sex, date of birth, age, race, and ethnicity. 
• Vital signs: blood pressure, pulse, respiration, temperature, height and weight. 
• Physical examination (complete) and ECOG (Appendix C). 
• Visual acuity assessment by Snellen eye chart or comparable eye chart. 
• Single ECG. 
• Relevant medical and cancer history will be completed through consent (all 
findings recorded on the medical history electronic case report form [eCRF]). 
• Documentation of concomitant and prior medications. 
• Adverse Events related to Screening procedures and any SAEs reporting. 
• Serum or urine pregnancy test (in women of childbearing potential). 
• Local laboratory values, including CBC (with differential, platelets, reticulocyte 
count), serum chemistry, serum uric acid, phosphorous, haptoglobin, D-dimer, 
thrombin time, plasma fibrinogen, PT/INR, aPTT, and urinalysis.  (See .) 
• Local laboratory Type and Screen (ABO/Rh) and DAT.  (Details are provided in 
Section 7.3.4). 
• Local laboratory Peripheral Blood Smears.  (Details are provided in 
Section 7.3.5). 
• ECOG performance status. 
• Tumor biopsy (within 2 weeks prior to first dose of drug): strongly encouraged for 
Phase 1b, mandatory for Phase 2.  Archival tumor tissue may be collected by the 
sponsor for correlative studies.  The tissue block is preferred, but if not available 
at least 10 unstained slides are suggested. 
• Response assessment:  diagnostic imaging.  (Historic imaging may be used for 


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screening if performed within 30 days of the first dose of Hu5F9-G4; details are 
provided in Section 10). 
• Tumor molecular profile if available including:  Microsatellite Instability status 
(MSI-High, MSI-Low, MSI-Stable, or unknown), Primary tumor sidedness (Left, 
Right, or unknown), BRAF V600E mutation (Yes, no, or unknown), KRAS 
mutation status (wild-type, mutant or unknown), NRAS status (wild-type, mutant, 
or unknown), PIK3CA mutation analysis (yes, no, or unknown). 
Screening assessments will be completed within a 30-day Screening period prior to 
the enrollment.  Screening assessments may be repeated during the 30-day 
Screening period.  Screening assessments may be used for 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 30-day 
Screening period. 
7.3. 
Description of Study Procedures 
Refer to SOA Table 4 through  for timing of study procedures. 
7.3.1. 
Physical Examination/Visual Acuity 
Complete physical exam should be performed at Screening.  Thereafter, 
symptom-directed physical exams are acceptable and may also include routine 
examination of the skin (including fingers, toes, and ears) and CNS.  For patients 
who have a change in visual acuity of 3 lines or more on a Snellen chart or 
comparable eye chart, an ophthalmologist should be consulted for additional 
evaluation. 
7.3.2. 
Vital Signs 
Vital signs should include heart rate, respiratory rate, blood pressure, temperature, 
and weight.  Height should be recorded during Screening only.  Weight should be 
recorded during Screening and on Day 1 of each cycle. 


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7.3.3. 
Electrocardiographs 
One ECG will be performed at screening.  Triplicate ECGs will be performed before 
the cetuximab dose (within 2 hours of infusion) and within 30 minutes of the end of 
Hu5F9-G4 infusion for Phase 1b only. 
7.3.4. 
Type and Screen (ABO/Rh), DAT 
Due to the risk of developing anemia, blood phenotyping, type and screen 
(ABO/Rh), and direct antiglobulin test (DAT) should be performed at Screening prior 
to exposure to Hu5F9-G4:  Full phenotyping (if not transfused in last 3 months) – 
ABO, Rh, D, C, E, Kell, Kidd, Duffy, MNS, and antibody screen.  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.  Details are provided in Table 11. 
7.3.5. 
Peripheral Blood Smear Assessment 
Peripheral smears will be collected prior to selected study drug infusions and 
assessed for the presence of hemagglutination, in addition to standard cell 
morphology assessment.  Slides should be processed and assessments should 
occur in accordance with the local laboratory's standard reporting timelines. These 
samples should be collected from the arm contralateral to the arm being used for 
drug infusion, if 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.  
 
 
. 
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7.3.6. 
Pregnancy Test 
Pregnancy tests are 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).  A urine or serum pregnancy test is required 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 done within the 72 hours prior to 
dosing. Pregnancy tests will be obtained every 8 weeks. 
7.3.7. 
Adverse Events 
At each visit all AEs observed by the Investigator or reported by the patient that 
occur after the first dose of study drugs through 30 days after the last dose of study 
drugs are to be reported using the applicable electronic case report form (eCRF; 
Section 9.3.1).  AEs that occur prior to assignment of 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 investigational product, Investigators should 
report any SAEs they assess as related to Hu5F9-G4 or cetuximab. 
7.3.8. 
Concomitant Medications 
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.  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 electronic case report form (eCRF). 
7.4. 
End of Treatment Visit 
End of Treatment Visit to be completed within 1 week of the decision to end 
treatment with Hu5F9-G4. 


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• Pharmacokinetic sample collection (for Phase 1b only).  PK samples will be 
collected for Hu5F9-G4 and cetuximab. 
• Correlative Studies 
• Antidrug Antibodies  
• CD47 Receptor Occupancy (only if End of Treatment Visit occurs prior to 
Cycle 2). 
• Response Assessment, if not performed within the last 4 weeks.  (Details are 
provided in Section 10) 
• Adverse Events 
• Concomitant medications 
7.5. 
Safety Follow-up Visit 
Safety Follow-up visit to be completed within 30 days (± 1 week) after the last dose 
of Hu5F9-G4. 
• Local Laboratory 
o CBC (w differential, platelets, reticulocyte count) 
o Serum chemistry 
o Haptoglobin, D-Dimer, thrombin time, and plasma fibrinogen 
o PT/INR, aPTT 
• Local laboratory Peripheral Blood Smear 
• Serum or urine pregnancy test (in women of childbearing potential) 
• Pharmacokinetic sample collection for Hu5F9-G4 and cetuximab 
• Antidrug Antibodies 
• ECOG performance status Appendix C 
• Vital signs 
o blood pressure 
o pulse 
o respiration 
o temperature 
o weight 


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• Adverse Events 
• Concomitant medications 
• Physical examination (symptom-directed) 
• Response Assessment (± 1 week), if not performed within the last 4 weeks 
(Section 10) 
7.6. 
Long-term Follow-up 
Patient will be followed until disease progression or until they begin a new 
anti-cancer therapy. 
• Response assessment (± 1 week), every 8 weeks (Section 10) 
• Correlative studies 
For patients who achieve a partial or complete response while on study, a repeat 
disease assessment will be obtained at the time of disease progression whenever 
possible.  These assessments include: 
• Blood sample for correlative studies 
• 
 
Following the Safety Follow-up Visit, patients with ongoing drug-related AEs and 
SAEs will be followed for safety.  If any study drug-related AEs or SAEs are ongoing 
after the Safety Follow-up Visit, follow-up with the patient will occur at least every 
4 weeks until resolution to baseline or stabilization of these events, unless the 
patient starts another anti-cancer therapy.  Follow-up will stop when a patient begins 
another anti-cancer therapy. 
7.7. 
Survival Follow-up 
All patients who permanently discontinue all study treatment for disease progression 
(according to the RECIST Version 1.1 Criteria; Section 10), clinical progression, 
unacceptable toxicity, partial withdrawal of consent, or administrative decision, will 
be contacted during a clinic visit or by telephone to assess survival, disease 
progression (if not documented previously), and the commencement of new cancer 
therapy following the last administration of study drugs.  Patients will be contacted 
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every 3 months (± 1 month) from the date of the safety follow-up visit, until 
60 months from the date that the last patient is enrolled into the study or full 
withdrawal of consent.  For any patient who dies during this period, the 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.  Public records may also be used to obtain survival 
information if the patient cannot be reached. 
7.8. 
Safety Assessments 
Analytes to be assessed by the local laboratory or specialty laboratories are 
presented in Table 11. 
 


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Table 11. 
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 
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 
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 
Correlative studies a 
Pharmacokinetics a 
CD47 Receptor 
Occupancy a,b 
ADAs a 
 


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• RBC abnormalities 
• Platelet Aggregation 
Note:  Refer to Section 7.1 Schedule of Assessment tables for collection time points. 
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; T4 = thyroxine; TSH =  thyroid-stimulating hormone; WBC = white blood cells. 
a. These assays may be performed at a specialty laboratory.  
b.  Beginning with Protocol Amendment 3, these samples will no longer be collected. 
 
 


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7.9. 
Efficacy Assessments 
Appropriate cancer staging assessments should be performed.  Imaging 
assessments are to be conducted according to the RECIST Version 1.1 Criteria for 
solid tumors (Section 10.1; Appendix D) and iRECIST (Seymour 2017).  The same 
imaging modality used at Screening should be used throughout the study whenever 
possible.  It is understood that some circumstances may require a different imaging 
modality.  An alternate imaging modality is acceptable and may be performed at the 
Investigator’s discretion. 
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 
treatment termination, unless a prior radiographic assessment has been performed 
within the prior 4 weeks or a prior response assessment documented PD 
(progressive disease). 
7.10. Immunogenicity 
Peripheral blood for immunogenicity assessments for antidrug antibodies against 
Hu5F9-G4 will be collected on Days 1 and 8, and then on Day 1 of all subsequent 
cycles; at the End of Treatment Visit; and at the Safety Follow-up Visit.  When 
collected on the day of study drugs dosing, the blood sample must be collected 
before dose administration.  A precise, sensitive, and reproducible qualitative 
electrochemiluminescent (ECL) assay will be used to measure antibodies to 
Hu5F9-G4 in serum samples.  This assay has been validated in cynomolgus 
monkey serum and has been used for the IND-enabling non-human-primate 
toxicology study for Hu5F9-G4 (PR013/20044845) and in Phase 1 clinical trials with 
Hu5F9-G4 (Studies SCI-CD47-001 and SCI-CD47-002).  For patients who have 
tested positive for antidrug antibodies (ADA), the impact of ADA on PK, safety, and 
biologic activity will be assessed.  Neutralizing antibodies to Hu5F9-G4 will also be 
assessed for patients who test positive for ADA.  Antidrug antibodies to cetuximab 
may be assessed if the CTSC or Sponsor determines such testing is needed. 


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7.11. Pharmacodynamic and Biomarker Assessments 
CD47 Receptor Occupancy 
Testing for CD47 receptor occupancy on select target cells enables 
pharmacodynamic testing of Hu5F9-G4 to inform both safety and efficacy 
parameters.  First, the degree of saturation of CD47 receptors on red blood cells 
serves as a pharmacodynamic assessment for degree of anemia.  Second, CD47 
receptor occupancy on WBCs and circulating or bone marrow-resident lymphoma 
cells provides information on level of CD47 saturation of the internal CD47 tissue 
sink and drug exposures on tumor cells, respectively.  Samples for CD47 Receptor 
Occupancy studies in the peripheral blood will be collected as described in the 
schedule of assessments (Section 7.1) and were planned for both the Phase 1b and 
Phase 2 parts of the study.  Beginning with Protocol Amendment 3, and with 
approval from the  CTSC, CD47 receptor occupancy studies were removed from the 
Phase 2 assessments. 
Correlative Blood Samples 
Correlative studies will be performed on peripheral blood samples to determine the 
biologic activity of Hu5F9-G4 in combination with cetuximab on circulating immune 
cells.  These studies that may include, but are not limited to, investigations in plasma 
cytokine levels, characterization of circulating T cells, and other studies.  Where 
applicable, blood samples will be collected as described in Table 9.  If at any point in 
the study the CTSC determines that sufficient correlative data have been generated, 
it may halt the collection and analysis of these samples. 
Tumor Biopsies 
Tumor biopsies will be obtained during both the Phase 1b and Phase 2 parts of the 
study.  
.  For the Phase 2 part, 
tumor biopsies are mandatory, unless the Investigator determines that it 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 obtained 
prior to treatment (within 2 weeks before the first dose of drug) and on Cycle 2 Day 8 
PPD


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(± 2 weeks).  Core biopsies may be collected for these timepoints; however 
excisional biopsies, where possible, are preferred over core biopsies.  Archival 
tumor tissue may be collected by the sponsor for correlative studies.  The tissue 
block is preferred, but if not available at least 10 unstained slides are suggested. 
In addition, for patients who achieve a partial or complete response while on study, a 
repeat tumor biopsy will be collected at the time of disease progression, whenever 
possible.  
 
 
PPD


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8. STUDY DISCONTINUATION 
8.1. 
Withdrawal of Patients from Study Drug Treatment 
Patients (or a legally acceptable representative) may decline to continue receiving 
study drugs at any time during the study.  The patient’s health and welfare is the 
primary consideration in any determination to discontinue study drugs treatment.  
Patients who withdraw from study drugs during the treatment period should be 
encouraged to return for an End of Treatment Visit for evaluation of safety within 
1 week of the decision to end Hu5F9-G4 treatment.  The studies to be performed at 
end of treatment are listed in the Schedules of Assessments, Section 7.1.  It is 
strongly encouraged that patients return for their Safety Follow-up Visit 30 days 
(± 1 week) after their last dose of study drugs.  The Safety Follow-up Visit 
assessments are described in Table 6.  All patients who withdraw from study drugs 
treatment will be followed for disease response and survival. 
Reasons for patient withdrawal from study drugs treatment may include, but are not 
limited to, the following:  
• Tumor progression, including confirmed tumor progression according to iRECIST 
• Unacceptable toxicity 
• Clinically significant change in the patient’s status that precludes further 
treatment (e.g, pregnancy or other AE) 
• Patient’s request, with or without a stated reason 
• Investigator or treating physician decision in the absence of any of the above. 
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 drugs 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 
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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, the 
following: 
• Death 
• Withdrawal of consent 
• Lost to follow up 
• Study termination 
8.3. 
Study Termination 
Forty Seven Inc. reserves the right to terminate the study at any time.  Both 
Forty Seven Inc. 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 
early termination and send a copy of the notification to Forty Seven Inc. 


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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; ECGs and physical exams; and the results from other protocol-specified tests 
that are deemed critical to the safety evaluation of the combination of study drugs. 
Forty Seven Inc. or its designee is responsible for reporting relevant SAEs to the 
Competent Authority, other applicable regulatory authorities, and participating 
Investigators, in accordance with 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). 
• AEs that occur prior to administration of the study drug that are related to a 
protocol-mandated intervention (e.g., invasive procedures such as biopsies). 
• Preexisting medical conditions, judged by the Investigator to have worsened in 
severity or frequency or changed in character during the protocol-specified AE 
reporting period. 
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) 


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• 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 investigational product(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] per 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. 
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 and protocol 
instructions. SAEs must be reported to the Sponsor or designee within 24 hours of 
the Investigator becoming aware of the event. 


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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 applies). 
After initiation of any the study drugs, all AEs and SAEs regardless of attribution will 
be collected until 30 days following the last dose of the last study drug received or 
the Safety Follow up Visit (whichever is later), or when the patient begins an 
alternate anti-cancer therapy. 
At any time, even after 30 days after the last dose of the last study drug received or 
the Safety Follow up Visit, Investigators are to report SAEs that they assess to be 
related to one of the study drug (Hu5F9-G4 and/or cetuximab received as part of this 
study). 
The Investigator must follow all unresolved SAEs and study drug-related AEs until 
the events are resolved (back to baseline) or stabilized, are determined to be 
irreversible by the Investigator, the Medical Monitor deems it necessary after the end 
of the study, the patient initiates alternate therapy for their cancer, or the patient is 
lost to follow-up. Resolution of AEs and SAEs (with dates) should be documented on 
the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification (SDV). 
The Sponsor or its designee may follow up by telephone, fax, electronic mail, and/or 
a monitoring visit to obtain additional case details (e.g., hospital discharge summary, 
consultant report, or autopsy report) deemed necessary to appropriately evaluate 
the SAE report. 
9.2.2. 
Eliciting Adverse Events 
A consistent methodology of non-directive questioning for eliciting AEs at all patient 
evaluation timepoints should be adopted.  Examples of non-directive questions 
include: 
“How have you felt since your last clinic visit?” 


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“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. 
For each AE and SAE recorded on the applicable eCRF, the Investigator will make 
an assessment of seriousness, severity, and causality (seriousness criteria are 
provided in Section 9.1.2.).  A causality assessment will be made for both Hu5F9-G4 
and cetuximab individually. 
The AE grading (severity) scale (Appendix B) will be used for AE reporting and 
Table 12 provides additional guidance for AEs not specifically mentioned in CTCAE.  
Table 13 provides guidance for assessing the causal relationship to the study 
drug(s). 


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Table 12. 
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 B) 
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. 
 


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To ensure consistency of causality assessments, Investigators should apply the 
following general guidelines: 
Table 13. 
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 “Yes” or “No” causality assessment for 
individual AE reports, Forty Seven Inc. 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/concepts when recording AEs 
on the eCRF.  Colloquialisms and abbreviations should be avoided. 
A separate log line in the Adverse Event 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 on the eCRF 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.  If a diagnosis is subsequently established, it should 


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be reported to Forty Seven Inc. by subsuming the symptoms under the diagnosis 
and according to the eCRF Completion Guidelines . 
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 timepoints.  Such events should only be recorded once unless their 
severity increases.  If a persistent AE becomes more severe, 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 
timepoints and subsequently recurs.  All recurrent AEs should be recorded on the 
Adverse Event eCRF. 
9.3.1.4. 
Abnormal Laboratory Values 
Only clinically significant laboratory abnormalities and ECG results that require 
active management will be recorded as AEs on the eCRF (e.g., abnormalities that 
require study drugs dose modification or discontinuation, more frequent follow-up 
assessments, further diagnostic investigation, etc.). 


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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) must be recorded on the Adverse Event eCRF. 
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 
expeditiously 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, particularly in the absence of 
other signs and symptoms, record “[specific tumor 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 routinely be 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 should be 


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recorded as an SAE if the outcome is fatal in the absence of other signs and 
symptoms (Section 9.3.1.5), or if the Investigator assesses the disease progression 
to be related to one of the study drugs. 
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 it is a planned hospitalization or 
prolonged hospitalization to: 
• Perform an efficacy measurement for the study. 
• Undergo a diagnostic or elective surgical procedure for a preexisting 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.  This includes: 
Pregnancy 
Any pregnancy occurring in a patient or a patient’s partner during treatment with 
either study drug or within 6 months of last study drugs administration must be 
reported (Section 9.4.2) within 24 hours of becoming aware of it, using a Pregnancy 
Notification Form (provided in the Investigator Trial File).  If the pregnancy occurs in 
a patient’s partner, the Investigator must obtain consent from the patient’s partner 
before collecting any pregnancy-related information.  All pregnancies must be 
followed up until there is a pregnancy outcome using a pregnancy outcome form.  In 
the event that the neonate/s has/have abnormalities at birth, additional data will be 
collected regarding the abnormalities.  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 


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study drugs should be recorded and reported as an SAE within 24 hours of 
awareness (Section 9.4.2). 
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 9.4.2). 
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 methods 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) 
• Oral 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).  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, 
throughout the trial, and for 6 months after the last dose of cetuximab or 4 months 
after the last dose of Hu5F9-G4, whichever occurs later. 


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Male patients, who are sexually active with partners of child-bearing potential and 
have not had a vasectomy, must agree to take measures not to father children by 
using one acceptable method of contraception such as 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. 
It should be explained to the patient that if his partner is pregnant or breast-feeding 
when he is enrolled on the trial, the patient must use barrier method contraception 
(condom plus spermicidal gel) to prevent the unborn fetus or the baby from being 
exposed to the investigational product. 
Male patients must also refrain from sperm donation from the administration of the 
first dose of Hu5F9-G4, throughout the trial, and for 6 months after the last dose of 
Hu5F9-G4 or 6 months after the last dose of cetuximab, whichever occurs later. 
Overdose 
An overdose is a dose higher than that indicated in the protocol with or without an 
AE.  Any overdose must be recorded in the trial drug section of the eCRF. 
Abuse or Misuse 
Abuse or misuse of a study drug is use for nonclinical reasons, with or without 
experiencing an AE. 
9.4. 
Expedited Reporting Requirements for Serious Adverse Events 
9.4.1. 
Reporting Requirements for Fatal/Life Threatening SAEs Related to 
Investigational Products 
Any life-threatening (i.e., imminent risk of death) or fatal AE assessed as related to 
the study drug(s) that occurs while on study drugs should be submitted to the 
Medical Monitor with written case details on an SAE Form within 24 hours of 
awareness, as described in Section 9.4.2. 


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Medical Monitor Contact Information for Sites: 
Medical Monitor:  Gani Chico, M.D. 
Telephone No.:  650-352-4133 
Alternate Telephone No.:  415-806-3145 
Email:  gchico@fortyseveninc.com 
Alternate Medical Monitor Contact Information for Sites: 
Medical Monitor:  Mark Chao M.D., Ph.D. 
Telephone No.: 650-776-7388 
Alternate Telephone No.: 650-352-4141 
Email:  mchao@fortyseveninc.com 
9.4.2. 
Reporting Requirements for All SAEs  
Investigators will submit reports of all SAEs to the Safety CRO and Sponsor within 
24 hours of awareness, regardless of attribution according to the instructions 
provided by the Sponsor. 
The Sponsor or designee will report applicable serious adverse events and/or 
suspected unexpected serious adverse reactions (SUSARs) to regulatory 
authorities, Investigators/institutions, and central IRBs/IECs in compliance with 
reporting requirements according to local regulations and good clinical practice 
(GCP). 
The Investigator is to notify the appropriate local IRB/IEC of serious adverse events 
occurring at the site and other applicable adverse event reports  in accordance with 
local procedures and statutes. 
9.5. 
Type and Duration of Follow-up of Patients after Adverse Events 
The Investigator must follow all unresolved SAEs and study drug-related AEs until 
the events are resolved or stabilized, are determined to be irreversible by the 
Investigator, the patient initiates alternate therapy for their cancer, or the patient is 
lost to follow-up, whichever occurs first. Follow up will be conducted as described in 
Section 7.5.  Resolution of AEs and SAEs (with dates) should be documented on the 


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Adverse Event eCRF and SAE Report Form (if applicable) and in the patient’s 
medical record to facilitate SDV. 
The Sponsor or its designee may follow up by telephone, fax, electronic mail, and/or 
a monitoring visit to obtain additional case details (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 one of the study drugs (Hu5F9-G4 and/or cetuximab received as part of 
this study). 


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10. MEASUREMENT OF EFFECT 
10.1. Anti-cancer Effect 
Patients will be assessed for response using the RECIST Version 1.1 Criteria 
(Eisenhauer 2009; Appendix D) and iRECIST (Seymour 2017, Appendix D).  
The first response assessment will occur after 8 weeks of treatment.  Subsequent 
response assessments will occur every 8 weeks.  Tumor markers will be obtained, 
as appropriate, at baseline, and then every 4 to 8 weeks.  Finally, response 
assessment will be obtained at the End of Treatment Visit, unless a prior 
radiographic assessment has been performed within the last 4 weeks or a prior 
response assessment documented progressive disease.  Definitions of response 
parameters are provided in the subsections below. 
10.2. RECIST Version 1.1 
10.2.1. 
Evaluation of Lesions 
Response and progression will be evaluated in this study using RECIST Version 1.1 
Criteria, as detailed in Appendix D. 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or 
non-measurable as follows: 
• Measurable tumor lesions must be accurately measured in at least one 
dimension (longest diameter in the plane of measurement is to be recorded) with 
a minimum size of: 10 mm by computed tomography (CT) scan (CT scan slice 
thickness no greater than 5 mm; Appendix D). 
• 10 mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded as non-measurable). 
• 20 mm by chest X-ray. 
• To be considered pathologically enlarged and measurable, a lymph node must 
be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). 
• At baseline and in follow-up, only the short axis will be measured and followed. 


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Non-measurable lesions include lesions with longest diameter < 10 mm or 
pathological lymph nodes with < 15 mm short axis as well as truly non-measurable 
lesions.  Lesions considered truly non-measurable include: 
• Leptomeningeal disease 
• Ascites 
• Pleural or pericardial effusion 
• Inflammatory breast disease 
• Lymphangitic involvement of skin or lung 
• Abdominal masses/abdominal organomegaly identified by physical exam that is 
not measurable by reproducible imaging techniques 
10.2.2. 
Assessment of Target Lesion Response 
When more than 1 measurable lesion is present at baseline all lesions up to a 
maximum of 5 lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions.  Target lesions should 
be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements. 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to 
< 10 mm. 
Partial Response (PR):  At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters. 
Progressive Disease (PD):  At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum measured while on study (this includes 
the baseline sum if that is the smallest on study).  In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.  
However, because patients treated with immunotherapies may show 
pseudoprogression, patients with PD may continue investigational treatment through 


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RECIST Version 1.1-defined radiological progression of disease until disease 
progression is confirmed ≥ 4 weeks later (Nishino 2013; Hodi 2016) provided that all 
of the following apply:  absence of clinical symptoms or signs indicating clinically 
significant disease progression; no decline in performance status; absence of rapid 
disease progression, or threat to vital organs or critical anatomical sites (e.g., CNS 
metastasis, respiratory failure due to tumor compression, or spinal cord 
compression) requiring urgent alternative medical intervention; and no significant 
unacceptable or irreversible toxicities related to study treatment.  If the confirmation 
scan demonstrates pseudoprogression and not PD, the patient may continue on 
treatment until disease progression is confirmed.  The appearance of one or more 
new lesions is also considered progression according to RECIST Version 1.1 
guidelines, however patients who meet the above criteria for non-clinically significant 
disease progression may also continue treatment until disease progression is 
confirmed (Hodi 2016). 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters measured 
while on study. 
10.2.3. 
Assessment of Non-target Lesions 
CR:  Disappearance of all non-target lesions and normalization of tumor marker 
level.  All lymph nodes must be non-pathological in size (< 10 mm short axis). 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
PD:  Unequivocal progression of existing non-target lesions.  However, because 
patients treated with immunotherapies may show pseudoprogression, patients with 
PD may continue investigational treatment through RECIST Version 1.1-defined 
radiological progression of disease until disease progression is confirmed ≥ 4 weeks 
later (Nishino 2013, Hodi 2016), provided that all of the following apply:  absence of 
clinical symptoms or signs indicating clinically significant disease progression; no 
decline in performance status; absence of rapid disease progression or threat to vital 


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organs or critical anatomical sites (e.g. CNS metastasis, respiratory failure due to 
tumor compression, spinal cord compression) requiring urgent alternative medical 
intervention; and no significant unacceptable or irreversible toxicities related to study 
treatment.  If the confirmation scan demonstrates pseudoprogression and not PD, 
patients may continue on treatment until disease progression is confirmed. 
10.2.4. 
Assessment of Evaluable rather than Measurable Disease 
Patients with evaluable but non-measurable response will be assessed with the 
diagnostic study used to establish evaluable disease at least every 8 weeks.  
If serum tumor markers are being used to assess response, they are to be obtained 
every 4 to 8 weeks. 
10.3. iRECIST 
Detailed iRECIST Criteria are listed in Appendix D. More examples (Scenario A-F) of 
response evaluation by iRECIST are available in the supplementary appendix to 
iRECIST in Appendix D. 
10.3.1. 
iRECIST Response Assessment 
Overall response will also be assessed using iRECIST.  Immunotherapeutics may 
result in infiltration of immune cells leading to transient increase in the size in 
malignant lesions, or undetectable lesions becoming detectable.  The criteria are 
identical to those of RECIST 1.1 in many respects but have been adapted to account 
for instances where an increase in tumor burden, or the appearance of new lesions, 
does not reflect true tumor progression. 
Key differences are described below.  All responses defined using iRECIST criteria 
are designated with a prefix. iRECIST time-point and best overall responses will be 
recorded separately. 
10.3.1.1. 
Confirming Progression 
Unlike RECIST 1.1, iRECIST requires the confirmation of progression and uses the 
terms iUPD (unconfirmed progression) and iCPD (confirmed progression). 


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Confirmatory scans should be performed at least 4 weeks, but no longer than 
8 weeks after iUPD. 
iCPD is confirmed if further increase in tumor burden, compared to the last 
assessment, is seen as evidenced by one or more of the following: 
• Continued increase in tumor burden (from iUPD) where RECIST 1.1 
definitions of progression had been met (from nadir) in target, non-target 
disease or new lesions 
o Progression in target disease worsens with an increase of at least 
5 mm in the absolute value of the sum 
o Continued unequivocal progression in non-target disease with an 
increase in tumor burden 
o Increase in size of previously identified new lesion (s) (an increase of 
at least 5 mm in the absolute value of the sum of those considered to 
be target new lesions) or additional new lesions. 
• RECIST 1.1 criteria are met in lesions types (target or non-target or new 
lesions) where progression was not previously identified, including the 
appearance of additional new lesions. 
• If iUPD is not confirmed at the next assessment, then the appropriate 
response will be assigned (iUPD if the criteria are still met, but no 
worsening, or iSD, iPR or iCR if those criteria are met compared to 
baseline).  As can be seen in Table 14, the prior documentation of iUPD 
does not preclude assigning iCR, iPR, or iSD in subsequent time-point 
assessments or as best overall response (BOR) providing that iCPD is not 
documented at the next assessment after iUPD. 
10.3.1.2. 
New Lesions 
New lesions should be assessed and measured as they appear using RECIST 1.1 
criteria (maximum of 5 lesions, no more than 2 per site, at least 10 mm in long axis 
(or 15 mm in short axis for nodal lesions) and recorded as New Lesions-Target 


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(NLT) and New Lesion-Non-Target (NLNT) to allow clear differentiation from 
baseline target and non-target lesions. 
New lesions may either meet the criteria of NLT or NLNT to drive iUPD (or iCPD).  
However, the measurements of target lesions should NOT be included in the sum of 
measures of original target lesions identified at baseline. 
PD is confirmed in the New Lesion category if the next imaging assessment, 
conducted at least 4 weeks (but not more than 8 weeks) after iUPD confirms further 
progression from iUPD with either an increase of at least 5 mm in the absolute value 
of the sum of NLT OR an increase (but not necessarily unequivocal increase) in the 
size of NLNT lesions OR the appearance of additional new lesions. 
Table 14 
Time-point iResponse 
 
 
 
Time-point Response 
Target 
Lesions* 
Non-Target 
Lesions* 
New 
Lesions* 
No 
prior 
iUPD** 
Prior iUPD**; *** 
iCR  
iCR  
No  
iCR  
iCR  
iCR  
Non-iCR/Non-
iUPD  
No  
iPR  
iPR  
iPR  
Non-iCR/Non-
iUPD  
No  
iPR  
iPR  
iSD  
Non-iCR/Non-
iUPD  
No  
iSD  
iSD  
iUPD with 
no change 
OR 
decrease 
from last 
TP  
iUPD with no 
change OR 
decrease from last 
TP  
Yes  
NA  
NLs confirms iCPD if NLs were previously 
identified and increase in size (≥ 5 mm in 
SOM for NLT or any increase for NLNT) or 
number. If no change in NLs (size or 
number) from last TP, remains iUPD  
iSD  
iUPD  
No  
iUPD  
Remains iUPD unless iCPD confirmed 
based on further increase in size of NT 
disease (need not meet RECIST 1.1 
criteria for unequivocal PD)  
iUPD  
Non-iCR/Non-
iUPD  
No  
iUPD  
Remains iUPD unless iCPD confirmed 
based on:  
• 
further increase in SOM of at least 
5 mm, otherwise remains iUPD 


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Time-point Response 
Target 
Lesions* 
Non-Target 
Lesions* 
New 
Lesions* 
No 
prior 
iUPD** 
Prior iUPD**; *** 
iUPD  
iUPD  
No  
iUPD  
Remains iUPD unless iCPD confirmed 
based on further increase in:  
• 
previously identified T lesion iUPD 
SOM ≥5 mm and / or 
• 
NT lesion iUPD (prior assessment - 
need not be unequivocal PD) 
iUPD  
iUPD  
Yes  
iUPD  
Remains iUPD unless iCPD confirmed 
based on further increase in:  
• 
previously identified T lesion iUPD ≥5 
mm and / or  
• 
previously identified NT lesion iUPD 
(need not be unequivocal) and /or  
• 
size or number of new lesions 
previously identified 
Non-
iUPD/PD  
Non-iUPD/PD  
Yes  
iUPD  
Remains iUPD unless iCPD confirmed 
based on:  
• 
increase in size or number of new 
lesions previously identified 
Abbreviations: CR = complete response; iCPD = immune confirmed progressive disease; iCR = immune complete 
response; iPR = immune partial response; iSD = immune stable disease; iUPD = immune unconfirmed 
progressive disease; NL = new lesion; NLT = new lesion - target; NLNT = new lesion - non-target; 
NT = non-target; PD = progressive disease; PR = partial response; SD = stable disease; SOM = sum of 
measures; T = target; TP = time point. 
* 
Using RECIST 1.1 principles. If no pseudoprogression occurs, RECIST 1.1 and iRECIST categories for 
CR, PR and SD would be the same.  
** 
in any lesion category.  
*** 
previously identified in assessment immediately prior to this TP. 
All patients will have their iBOR from the start of study treatment until the end of 
treatment classified as outlined in Table 15. 


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Table 15 
iRECIST Best Overall Response (iBOR) 
TPR1  
TPR2  
TPR3  
TPR4  
TPR5  
iBOR  
iCR  
iCR, iPR, 
iUPD, NE  
iCR, iPR, 
iUPD, NE  
iUPD  
iCPD  
iCR  
iUPD  
iPR, iSD, NE  
iCR  
iCR, iPR, iSD, 
iUPD, NE  
iCR, iPR, iSD, 
iUPD, iCPD, 
NE  
iCR  
iUPD  
iPR  
iPR, iSD, 
iUPD, NE  
iPR, iSD, 
iUPD, NE, 
iCPD  
iPR, iSD, 
iUPD, NE, 
iCPD  
iPR  
iUPD  
iSD, NE  
PR  
iPR, iSD, 
iUPD, NE  
iPR, iSD, 
iUPD, iCPD, 
NE  
iPR  
iUPD  
iSD  
iSD, iUPD, NE  
iSD, iUPD, 
iCPD, NE  
iSD, iUPD, 
ICPD, NE  
iSD  
iUPD  
iCPD  
Anything  
Anything  
Anything  
iCPD  
iUPD  
iUPD  
iCPD  
Anything  
Anything  
iCPD  
iUPD  
NE  
NE  
NE  
NE  
iUPD  
Abbreviations: CR = complete response; iBOR = immune best overall response; iCPD = immune confirmed 
progressive disease; iCR = immune complete response; iPR = immune partial response; iSD = immune 
stable disease; iUPD = immune unconfirmed progressive disease; NE = not evaluable that cycle; 
PD = progressive disease; PR = partial response; TPR = time-point response. 
• 
Table assumes a randomized study where confirmation of CR or PR is not required.  
• 
NE = not evaluable that cycle.  
•• For patients with non-target disease only at baseline, only CR or non-CR/non-PD can be assigned at each 
TPR but is not shown in the table for ease of presentation. 
10.3.1.3. 
Response and Stable Disease Duration (RECIST 1.1 
and iRECIST) 
Response duration will be measured from the time measurement criteria for CR/PR 
or iCR/iPR (whichever is first recorded) are first met until the first date that recurrent 
or progressive disease is objectively documented, taking as reference the smallest 
measurements recorded on study (including baseline). 
Stable disease duration will be measured from the time of start of treatment until the 
criteria for progression are met, taking as reference the smallest sum on study 
(including baseline). 


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10.3.1.4. 
Methods of Measurement 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Assessments should be identified on a calendar schedule and should not be 
affected by delays in therapy.  While on study, all lesions recorded at baseline 
should have their actual measurements recorded at each subsequent evaluation, 
even when very small (e.g. 2 mm).  If it is the opinion of the radiologist that the lesion 
has likely disappeared, the measurement should be recorded as 0 mm.  If the lesion 
is believed to be present and is faintly seen but too small to measure, a default value 
of 5 mm should be assigned.  For lesions which fragment/split add together the 
longest diameters of the fragmented portions; for lesions which coalesce, measure 
the maximal longest diameter for the “merged lesion”. 
Clinical Lesions.  Clinical lesions will only be considered measurable when they are 
superficial and ≥ 10 mm as assessed using calipers (e.g., skin nodules).  For the 
case of skin lesions, documentation by color photography including a ruler to 
estimate the size of the lesion is recommended.  If feasible, imaging is preferred. 
Chest X-ray.  Chest CT is preferred over chest X-ray, particularly when progression 
is an important endpoint, since CT is more sensitive than X-ray, particularly in 
identifying new lesions.  However, lesions ≥ 20 mm on chest X-ray may be 
considered measurable if they are clearly defined and surrounded by aerated lung. 
CT, MRI.  CT is the best currently available and reproducible method to measure 
lesions selected for response assessment.  This guideline has defined measurability 
of lesions on CT scan based on the assumption that CT slice thickness is 5 mm or 
less.  When CT scans have slice thickness greater than 5 mm, the minimum size for 
a measurable lesion should be twice the slice thickness.  MRI is also acceptable in 
certain situations (e.g., for body scans).  Other specialized imaging or other 
techniques may also be appropriate for individual case.  For example, while PET 
scans are not considered adequate to measure lesions, PET-CT scans may be used 


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providing that the measures are obtained from the CT scan and the CT scan is of 
identical diagnostic quality to a diagnostic CT (with IV and oral contrast). 
Ultrasound.  Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement.  If new lesions are identified by ultrasound in the 
course of the study, confirmation by CT is advised. 
Endoscopy, Laparoscopy.  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, they can be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials 
where recurrence following complete response or surgical resection is an endpoint. 
Tumor Markers.  Tumor markers alone cannot be used to assess objective tumor 
response.  If markers are initially above the upper normal limit, however, they must 
normalize for a patient to be considered in complete response. 
Cytology, Histology.  These techniques can be used to differentiate between PR and 
CR in rare cases if required by protocol (for example, residual lesions in tumor types 
such as germ cell tumors, where known residual benign tumors can remain).  When 
effusions are known to be a potential adverse effect of treatment (e.g., with certain 
taxane compounds or angiogenesis inhibitors), the cytological confirmation of the 
neoplastic origin of any effusion that appears or worsens during treatment when the 
measurable tumor has met criteria for response or stable disease is advised to 
differentiate between response or stable disease and progressive disease. 


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11. STATISTICAL CONSIDERATIONS 
11.1. Analysis Sets 
Enrolled Analysis Set (ENS) – includes all enrolled patients. 
Typically, summary tables of disposition and protocol deviations will be performed on 
the ENS. 
DLT Analysis Set - includes all enrolled patients who receive at least 1 dose of 
Hu5F9-G4 or cetuximab and either experience a DLT or complete at least 
4 infusions of Hu5F9-G4 and 2 infusions of cetuximab. 
Patients who withdraw before completing the 4-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. 
Efficacy Analysis Set (EAS) - includes all enrolled patients who received at least 
1 dose of Hu5F9-G4. 
The analysis of ORR, DOR, DCR, PFS, OS, and TTP will be performed on the 
Efficacy Analysis Set. 
Safety Analysis Set (SAF) – includes all enrolled patients who receive at least 
1 dose of the study drugs. 
Safety analysis and demographics, etc. will be performed using the SAF. 
Per Protocol Analysis Set (PPS) – includes includes all enrolled patients who do 
not have any important or major protocol deviations that might affect the efficacy 
outcomes. 
A sensitivity analysis of ORR may be performed on the Per Protocol Analysis Set. 
PK Analysis Set (PAS) - includes all enrolled patients who receive at least 1 dose 
of study drugs and  have measurable concentrations of Hu5F9-G4 from PK blood 
samples. 


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11.2. Sample Size Determination 
The total number of patients in this trial will include as many as 112 patients.  This 
sample size includes the Phase 1b and Phase 2 parts of the study.  In Phase 1b, a 
standard 3+3 dose escalation design will be used to explore the MTD of the 
investigational study drug combination in patients with solid tumors.  An estimated 
32 patients will be enrolled in Phase 1b, depending on dose escalation and 
expansion. 
Phase 2 includes 2 arms, one comprising patients with KRAS mutant CRC and the 
other comprising patients with KRAS wild-type CRC, in which enrollment in one or 
both arms may be modified based on emerging data.  A total of 88 patients 
(44 patients per arm) will be enrolled in Phase 2, assuming progression to Stage 2 
for both arms.  This sample size estimate was determined using a one-sided alpha 
level of 0.10 and a power of 0.80 based on a null hypothesis of 5% response rate 
compared to an alternative hypothesis of 15% for each cohort. 
11.3. Statistical Methods 
All analyses will be descriptive in nature.  Descriptive statistics will be provided for all 
safety and efficacy endpoints. 
All analyses will be conducted separately for patients in Phase 1b and Phase 2 parts 
of the study.  However, safety analyses may be conducted for patients in both Phase 
1b and Phase 2.  In addition, efficacy analyses will be conducted separately for the 
two cohorts in Phase 2. 
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 confidence intervals for primary and secondary efficacy 
endpoints.  For time-to-event variables, the Kaplan-Meier (KM) estimates and 
corresponding two-sided 95% confidence intervals for the median and quartiles will 
be provided.  The KM plot may also be provided. Details regarding the statistical 


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analysis to be conducted, including the handling of missing data and patient 
withdrawal, will be provided in the SAP. 
11.3.1. 
Efficacy Analyses 
Endpoints used in the efficacy analysis are ORR, DOR, DCR, PFS, OS, and TTP. 
11.3.1.1. 
Objective Response Rate 
Objective response is defined as CR+PR determined by RECIST v 1.1 (primary 
efficacy) and iCR+iPR determined by iRECIST (secondary efficacy) separately.  
ORR is defined as the proportion of patients with objective response in the Efficacy 
Analysis Set. 
A sensitivity analysis of ORR will be conducted on the Per Protocol Analysis Set if 
more than 10% of patients in the Efficacy Analysis Set are excluded from the Per 
Protocol Analysis Set. 
11.3.1.2. 
Disease Control Rate  
Disease control is defined as CR+PR+SD determined by RECIST v 1.1. DCR is 
defined as the proportion of patients with disease control in the Efficacy Analysis 
Set. 
11.3.1.3. 
Duration of Response 
DOR is measured from when the first (objective) response is met (i.e., CR or PR) 
until the first date of objectively documented progressive disease.  Patients who do 
not have objectively progressive disease will be censored at their last documented 
progression-free date. 
11.3.1.4. 
Progression-free Survival 
PFS is measured from dose initiation until the first date of objectively documented 
progression disease or death.  Patients who do not have objectively documented 
progression disease AND not died will be censored at their last documented 
progression-free date. 


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11.3.1.5. 
Overall Survival 
OS is measured from dose initiation until death.  Patients who did not die will be 
censored at their last known alive date. 
11.3.1.6. 
Time to Progression 
TTP is measured from dose initiation until the first date of objectively documented 
progressive disease. Patients who do not have objectively documented progressive 
disease will be censored at their last documented progression-free date. 
Note: Term “objectively documented progressive disease” above refers to PD in the 
overall response evaluation form. 
11.3.2. 
Pharmacokinetic/Pharmacodynamics Analyses 
11.3.2.1. 
Pharmacokinetic Analyses 
PK analysis will be conducted for Hu5F9-G4 and cetuximab using the PAS.  Based 
on the distinct MOAs of Hu5F9-G4 and cetuximab, drug-drug PK interactions are not 
expected.  Thus, samples for PK analysis for cetuximab will be biobanked and will 
be analyzed based on CTSC recommendation. 
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.  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. 
The PK parameters to be assessed are presented in Table 16. 


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Table 16. 
Noncompartmental Pharmacokinetic Parameters 
AUClast 
The AUC from time zero to the last measurable concentration sampling time (tlast) (mass 
× time × volume ˗ 1) 
AUCinf 
The AUC from time zero to infinity (mass × time × volume ˗ 1) 
AUCtau 
The AUC calculated to the end of a dosing interval (tau) at steady-state (amount × time 
× volume ˗ 1) 
Cmax 
The maximum (peak) observed plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (mass × volume ˗ 1) 
Tmax 
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (time) 
T1/2 
The elimination half-life associated with the terminal slope (λz) of a semi logarithmic 
concentration-time curve (time).  Use qualifier for other half-lives 
CL 
The total body clearance of drug from the plasma (volume × time ˗ 1) 
Vz 
The apparent volume of distribution during terminal phase (associated with λz) (volume) 
PAS will be used in all PK data analysis and PK summary statistics, except for the 
dose-exposure analysis for Phase 1b. 
Pharmacokinetic Variables 
The following parameters will be determined by profile using non-compartmental 
method(s) for Hu5F9-G4: 
• AUCinf 
• AUC0-168h 
• Cmax 
• Tmax 
• T1/2 
• CL 
• Vz 
Biofluid concentrations will be expressed in mass per volume units.  All 
concentrations below the limit of quantitation or missing data will be reported as 
such in the concentration data listings.  Concentrations below the limit of quantitation 
will be treated as zero in summary statistics. 
Descriptive statistics of all PK parameters will include arithmetic and geometric 
mean, median, SD, CV, geometric CV, minimum and maximum.  Zero 


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concentrations will not be included in the geometric mean calculation.  Since Tmax is 
generally evaluated by a nonparametric method, median values and ranges will be 
provided for this parameter. 
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 handled as zero in summary statistics, 
and reported as is in data listings.  Any missing PK parameter data will not be 
imputed. 
11.3.2.2. 
Dose Proportionality 
The analysis of dose proportionality will be conducted for the AUC and Cmax of 
Hu5F9-G4 using a power model on log-transformed scale.  The log-transformed PK 
parameters will each be regressed onto a fixed factor for log (dose).  The 90% 
confidence interval (CI) of the slope for each PK parameter will be computed from 
the model and presented in a summary table. 
11.3.2.3. 
Immunogenicity Analyses 
The rate and magnitude of anti-Hu5F9-G4 antibody positivity will be evaluated for 
individual patients, for all patients in the Phase 1b and 2 parts of the trial, and for the 
pooled patient population.  
 
 
  
Immunogenicity analysis will also be performed for cetuximab.  However, it is not 
expected that Hu5F9-G4 will impact the immunogenicity of cetuximab and vice 
versa. 
PPD


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Immunogenicity:  Exposure and/or Adverse Event Relationship 
The concentration-versus-adverse event/immunogenicity relationship will be 
explored graphically, tabulated and, if appropriate, evaluated by a mixed effects 
model in order to characterize a relationship between the changes from screening 
immunogenicity presence and serum concentration of Hu5F9-G4. 
In addition, the potential correlation between immunogenicity and other endpoints 
(major safety, efficacy, and biomarker parameters) may be evaluated.  This will be 
done in 2 steps.  First, a descriptive analysis will be performed graphically between 
immunogenicity change from screening values and major safety, efficacy, and 
biomarker parameters (either as categories or continuous variables).  Second, for 
any potential correlation identified, further investigation will be performed using a 
mechanism-based modeling approach, as appropriate. 
11.3.2.4. 
Pharmacodynamic and Biomarker Analyses 
 
 
 
 
 
11.3.3. 
Safety Analyses 
The statistical analysis of safety will be conducted for patients in the SAF. 
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, treatment-emergent adverse events (TEAEs: AEs 
worsening or occurring during or after a patient’s first exposure to study drugs), vital 
signs, physical examinations, laboratory, receptor occupancy, and antidrug antibody 
assessments.  Adverse events will be coded using Medical Dictionary for Regulatory 
Activities (MedDRA, Version 17.1 or later) and grouped by system organ class and 
preferred term. 
PPD


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Data will be presented by Phase 1b dose cohort and Phase 2 arm, 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 day/study day interval corresponding to dose 
administrations within each dose cohort. 
11.3.3.1. 
Adverse Events 
For the safety Analysis Set, AEs that occurred during Screening, but before 
exposure to study drugs will be reported in the AE line listings and appropriately 
identified as non-TEAEs.  Summary tables of TEAEs 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 will also be 
tabulated using Investigator assessment of the relationship to study drugs (related or 
not related).  SAEs, including deaths, will be summarized and/or listed for each dose 
cohort and for all dose cohorts combined.  TEAEs resulting in withdrawal from study 
drugs 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. 
Adverse events and SAEs occurring during Screening will be reported separately for 
patients in the Screened-only Set with line listings and/or summary tables, along with 
relevant demographic data collected. 
11.3.3.2. 
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. 
11.4. Interim Analysis 
An interim analysis would be conducted on the first 15 efficacy evaluable patients for 
each cohort in Phase 2. If median PFS is no more than 2 months and objective 


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response rate is less than 10%, then there would be no further enrollment into the 
cohort. CTSC would decide whether or not to further expand a cohort based on the 
totality of the efficacy as well as safety data. 


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12. ETHICAL AND ADMINISTRATIVE CONSIDERATIONS 
12.1. Compliance Statement 
This study will be conducted in accordance with the protocol and with US Food and 
Drug Administration (FDA) and the International Conference on Harmonisation (ICH) 
good clinical practice (GCP) guidelines, the Declaration of Helsinki, and any 
applicable local health authority and Institutional Review Board (IRB)/Independent 
Ethics Committee (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) 
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 


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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 Forty Seven Inc., 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 informed consent form, 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 
informed consent form must be received by Forty Seven Inc. 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 
Forty Seven Inc., in accordance with local procedures. 
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 Forty Seven Inc. 


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12.4. Informed Consent and Human Subject Protection 
An initial sample informed consent form 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 Forty Seven Inc. 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 subject, to the subject’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 
informed consent form 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 informed consent form is to be retained in 
accordance with institutional policy, and a copy of the signed consent form is to be 
provided to the patient or legally acceptable representative. 


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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 informed consent form to the patient and must allow for questions.  Thereafter, 
both the patient and the witness must sign the informed consent form 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 Forty Seven Inc., including the following: 
• Subjects are to be identified by a unique subject 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 subject identification 
number, include the age at time of enrollment. 
• For Serious Adverse Events reported to Forty Seven Inc., patients are to be 
identified by their unique subject identification number, initials (for faxed reports, 
in accordance with local laws and regulations), and date of birth (in accordance 
with local laws and regulations). 
• Documents that are not submitted to Forty Seven Inc. (e.g., signed informed 
consent forms) are to be kept in confidence by the Investigator, except as 
described below. 
In compliance with the Code of Federal Regulations (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 Forty Seven Inc. 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 
Forty Seven Inc. 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 
Within the United Kingdom (UK), the Medicines for Human Use (Clinical Trials) 
Regulations require the Sponsor to notify any "serious breaches" to the Medicines 
and Healthcare products Regulatory Agency (UK) (MHRA) within 7 days of the 
Sponsor becoming aware of the breach.  A serious breach is defined as “A breach of 
GCP or the trial protocol which is likely to effect to a significant degree:  
• the safety or physical or mental integrity of the patients of the trial, or 
• the scientific value of the trial 
Investigators must notify Forty Seven Inc. immediately if any serious breach of GCP 
is suspected. 
If there is any proof of fraud this must also be reported to Forty Seven Inc.  All 
instances of confirmed clinical trial fraud occurring at sites in the UK will be treated 


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according to the procedure for dealing with a serious breach and must be reported to 
the MHRA within 7 days of the Sponsor becoming aware. 
12.8. Study Monitoring 
The Forty Seven Inc. 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 Forty Seven Inc. 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 Forty Seven Inc. 
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 Forty Seven Inc. 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 


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who withdraw prior to completion of all protocol-required visits and are unable or 
unwilling to continue the SOA (Section 7.1), the Investigator may search publically 
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 electronic Case Report Form 
(eCRFs) (or paper Case Report Forms [CRFs]) and source documentation as part of 
the case histories.  Forty Seven Inc. 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 


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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. 
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 Forty Seven Inc. 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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12.12. Long-term Retention of Samples for Additional Future Research 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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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. 
PPD


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13. REFERENCES 
Allegra CJ, Jessup JM, Somerfield MR, et al. American society of clinical oncology 
provisional clinical opinion: testing for KRAS gene mutations in patients with 
metastatic colorectal carcinoma to predict response to anti–epidermal growth factor 
receptor monoclonal antibody therapy. J Clin Oncol 2009;27(12):2019-2096. 
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. 
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. 
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. 
Fan Z, Masui H, Atlas I, et al. Blockade of epidermal growth factor receptor function 
by bivalent and monovalent fragments of 225 anti-epidermal growth factor receptor 
monoclonal antibodies. Cancer Res 1993;53:4322-4328. 


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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. 
Hodi FS, Hwu WJ, Kefford R, et al. Evaluation of immune-related response criteria 
and RECIST v1.1 in patients with advanced melanoma treated with pembrolizumab. 
J Clin Oncol. 2016;34(13):1510-1517. 
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. 
Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from 
cetuximab in advanced colorectal cancer. N Engl J Med 2008;359:1757-65. 
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. 
Kurai J, Chikumi H, Hashimoto K, et al. Antibody-dependent cellular cytotoxicity 
mediated by cetuximab against lung cancer cell lines. Clin Cancer Res 
2007:13(5):1552-1561. 
Lee MS and Kopetz S. Current and future approaches to target the epidermal growth 
factor receptor and its downstream signaling in metastatic colorectal cancer. Clinical 
Colorectal Cancer 2015;14(4):203-18. 
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. 
Nishino M, Giobbie-Hurder A, Gargano M, et al. Developing a common language for 
tumor response to immunotherapy: immune-related response criteria using 
unidimensional measurements. Clin Cancer Res. 2013;19(14):3936. 
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. 
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. 


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Seymour L, Bogaerts J, Perrone A, et al. iRECIST: Guidelines for response criteria 
for use in trials testing immunotherapeutics. Lancet Oncol. 2017 Mar; 18(3): 
e143-e152. 
Siegel RL, Miller KD, and Jemal A. Cancer statistics, 2016. CA Cancer J Clin 
2016;66(1):7-30. 
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. 
Vaughn CP, Zobell SD, Furtado LV, et al. Frequency of KRAS, BRAF, and NRAS 
mutations in colorectal cancer. Genes Chromosomes Cancer 2011;50(5):307-312. 
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. 


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14. APPENDICES 
Appendix A: 
Cetuximab (Erbitux®) Prescribing Information 
 
Available online: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/125084s225lbl.pdf 
Accessed 7 June 2016 
 


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Appendix B: 
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_8.5x11.pdf 
 
Accessed 06 August 2018 


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Appendix C: 
ECOG Performance Status 
 
Eastern Cooperative Oncology Group Scale of Performance Status 
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. 
 
Karnofsky Performance Status 
Publication: 
Karnofsky D, Burchenal J, The clinical evaluation of chemotherapeutic agents in 
cancer. In: MacLeod C, ed. Evaluation of Chemotherapeutic Agents. New York, NY: 
Columbia University Press; 1949:191–205. 
http://ecog-acrin.org/resources/ecog-performance-status 
Accessed 06 August 2018 


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Appendix D: 
RECIST Version 1.1 and iRECIST Guidelines  
Publication: 
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;45:228 – 
247 
http://ctep.cancer.gov/protocolDevelopment/docs/recist_guideline.pdf 
Accessed 06 August 2018 
Seymour L, Bogaerts J, Perrone A, et al. iRECIST: Guidelines for response criteria 
for use in trials testing immunotherapeutics. Lancet Oncol. 2017 Mar; 18(3): 
e143-e152. 
http://recist.eortc.org/wp-content/uploads/2017/03/Manuscript_IRECIST_Lancet-
Oncology_Seymour-et-al_revision_FINAL_clean_nov25.pdf 
http://recist.eortc.org/wp-content/uploads/2017/03/Supplementary-
material_iRECIST_Seymour-et-al_revision_FINAL_clean_nov25.pdf 


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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 based on 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: 
5F9004 
Statistical Analysis Plan, Version 1.0 (12 Feb 2020) 
Page 1 
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STATISTICAL ANALYSIS PLAN 
TITLE: 
A PHASE 1B/2 TRIAL OF HU5F9-G4 IN COMBINATION WITH 
CETUXIMAB IN PATIENTS WITH SOLID TUMORS AND 
ADVANCED COLORECTAL CANCER 
 
PROTOCOL NUMBER: 
5F9004 
STUDY DRUG: 
Magrolimab (Hu5F9-G4) 
VERSION NUMBER: 
1.0 
SPONSOR: 
Forty Seven Inc 
PLAN PREPARED BY: 
 
DATE: 
12 February 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 


Statistical Analysis Plan, Version: 1.0 (12FEB2020) 
5F9004 
Confidential 
Ma rolimab 
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 
~PD 
Feb l <f-. 
..?o~ 
1PPD 
I 
Forty Seven Inc. 
[PPD 
-
/'l&£~2CJ 
PPD 
I 
Forty Seven Inc. 
Forty Seven Inc. 
2 


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TABLE OF CONTENTS 
APPROVAL .................................................................................................................................. 2 
TABLE OF CONTENTS ............................................................................................................... 3 
LIST OF TABLES ......................................................................................................................... 4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................ 5 
1 
INTRODUCTION ............................................................................................................. 6 
1.1 
Study Design ................................................................................................................... 6 
1.2 
Study Objectives and Endpoints ..................................................................................... 8 
1.3 
Sample Size Determination............................................................................................. 9 
2 
ANALYSIS SETS ............................................................................................................. 9 
3 
PATIENT INFORMATION .............................................................................................. 9 
3.1 
Patient Disposition .......................................................................................................... 9 
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 
Premedication ............................................................................................................... 11 
3.8 
Subsequent Lines of Anticancer Therapy ..................................................................... 11 
4 
EFFICACY ANALYSIS ................................................................................................. 11 
5 
PHARMACOKINETIC ANALYSES ............................................................................. 11 
5.1 
Pharmacokinetic Analysis ............................................................................................. 11 
5.2 
Immunogenicity Analysis ............................................................................................. 12 
6 
SAFETY ANALYSIS ...................................................................................................... 12 
6.1 
Extent of Exposure ........................................................................................................ 12 
6.2 
Adverse Events ............................................................................................................. 12 
6.3 
Deaths ........................................................................................................................... 13 
6.4 
Clinical Laboratory Evaluation ..................................................................................... 13 


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6.5 
Vital Signs ..................................................................................................................... 14 
6.6 
Physical Examination.................................................................................................... 14 
6.7 
Electrocardiogram ......................................................................................................... 14 
6.8 
Peripheral Blood Smear ................................................................................................ 14 
6.9 
Visual Acuity and Retinal Imaging............................................................................... 14 
7 
CHANGES TO PROTOCOL-SPECIFIED ANALYSES ............................................... 14 
8 
REFERENCES ................................................................................................................ 14 
LIST OF TABLES 
Table 1 
Study Treatment Dose and Schedule for Phase 1b ................................................ 7 
Table 2 
Study Treatment Dose and Schedule for Phase 2 .................................................. 7 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
5F9 
Hu5F9-G4, the experimental agent for this trial 
ADA 
antidrug antibodies 
ATC 
anatomical\therapeutic\chemical 
CR 
complete response 
CRC 
colorectal cancer 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTSC 
Clinical Trial Steering Committee 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
eCRF 
electronic case report form 
iRECIST 
modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1) for cancer 
immunotherapeutic trials 
ORR 
objective response rate 
OS 
overall survival 
PFS 
progression-free survival  
PK 
pharmacokinetic 
PR 
partial response 
PT 
preferred term 
QW 
every week  
Q2W 
every 2 weeks  
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2DS 
recommended Phase 2 dose and schedule 
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 and PK/ADA of the clinical trial described in 
the Forty Seven Inc. protocol for Study 5F9004 entitled “A Phase 1b/2 Trial of Hu5F9-G4 in 
Combination with Cetuximab in Patients with Solid Tumor and Advanced Colorectal Cancer” 
Amendment 3, dated 28 Sep 2018.  Analyses of biomarker data are out of scope of this SAP. 
Analysis methods specified in this document take precedence over those described in the protocol 
should there be any difference. 
1.1 
Study Design 
This trial is an open-label, multicenter Phase 1b/2 trial investigating the combination of 
magrolimab (Hu5F9-G4; hereafter referred to as 5F9) and cetuximab in patients with solid tumor 
and patients with advanced colorectal cancer (CRC).  The study will be conducted in 2 parts: 
• Dose escalation Phase 1b open to patients with solid tumors 
• Phase 2 study in patients with advanced/metastatic CRC whose tumors are either KRAS 
mutant or KRAS wild-type 
The Phase 1b dose escalation part of the study will be conducted using a standard 3 + 3 dose 
escalation design to determine the maximum tolerated dose, if one exists, and to identify a 
recommended Phase 2 dose and schedule (RP2DS) of 5F9 in combination with cetuximab.  The 
dosing levels and schedules in each cohort are described in Table 1.  
On all days on which both cetuximab and 5F9 are given, cetuximab will be given first.  5F9 will 
be given at least 1 hour after the cetuximab infusion is completed.  Each cycle lasts 28 days. 
Patients enrolled in the Phase 1b part of the study who have been on study for at least 8 weeks may 
have their dose escalated to a higher dose level if deemed safe at the discretion of the investigator 
and the Clinical Trial Steering Committee (CTSC). 
The Phase 2 part of the study will incorporate a safety run-in by treating 9 patients with KRAS 
wild-type tumors at the RP2DS.  If the tolerability of the regimen is confirmed in CRC patients 
after these 9 patients have completed the Dose-Limiting Toxicity (DLT) Assessment Period, the 
study will begin to accrue patients with advanced CRC who have KRAS mutant tumors and 
continue to accrue patients who have KRAS wild-type tumors and who are relapsed or refractory 
to an anti-EGFR antibody therapy.  Enrollment will be held after 15 efficacy-evaluable patients 
for each cohort are enrolled.  An interim analysis will be conducted.  The CTSC will convene to 
review and approve proceeding with full accrual for Phase 2.  The CTSC may also approve further 
enrollment and exploration of additional alternate Phase 2 doses that may enhance efficacy. 


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Table 1 
Study Treatment Dose and Schedule for Phase 1b 
Dose 
Cohort 
Dose Levels in Cycle 1 
5F9 Schedule 
in Cycle 2+a 
Day 1 
(5F9 priming 
dose) 
Day 8 
(5F9 maintenance dose + 
cetuximab loading dose)  
Day 15, 22 
(maintenance dose) 
1 
5F9 1 mg/kg 
5F9 10 mg/kg 
+ Cetuximab 300 mg/m2 
5F9 10 mg/kg 
+ Cetuximab 200 mg/m2 
QW 
2 
5F9 10 mg/kg 
+ Cetuximab 400 mg/m2 
5F9 10 mg/kg 
+ Cetuximab 250 mg/m2 
3 
5F9 20 mg/kg 
+ Cetuximab 400 mg/m2 
5F9 20 mg/kg 
+ Cetuximab 250 mg/m2 
4  
5F9 30 mg/kg 
+ Cetuximab 400 mg/m2 
5F9 30 mg/kg 
+ Cetuximab 250 mg/m2 
5b 
5F9 45 mg/kg 
+ Cetuximab 400 mg/m2 
5F9 45 mg/kg 
+ Cetuximab 250 mg/m2 
C2: QW 
C3+: Q2W 
Abbreviations:  C = cycle; QW = every week; Q2W = every 2 weeks. 
a 
Cetuximab is given on a weekly schedule. 
b 
A loading dose of 5F9 at 45 mg/kg is given on Day 11.  
 
The dose levels and schedules for 5F9 in each cohort are described in Table 2, in combination with 
cetuximab (a loading dose of 400 mg/m2 followed by a maintenance dose of 250 mg/m2 QW) in 
Phase 2. 
Table 2 
Study Treatment Dose and Schedule for Phase 2 
Cohort 
5F9 Dose Levels in Cycle 1 
5F9 Schedule 
in Cycle 2+a 
Day 1 
(5F9 priming 
dose) 
Day 8 
(5F9 maintenance dose + 
cetuximab loading dose)  
Day 15, 22 
(maintenance dose) 
KRASwt 
5F9 1 mg/kg 
5F9 30 mg/kg + Cetuximab 
400 mg/m2 
5F9 30 mg/kg + Cetuximab 
250 mg/m2 
Q2W 
KRASm Cohort 
1 
KRASm Cohort 
2b 
5F9 45 mg/kg + Cetuximab 
400 mg/m2 
5F9 45 mg/kg + Cetuximab 
250 mg/m2 
C2: QW 
C3+: Q2W 
Abbreviations:  C = cycle; KRASm = KRAS mutant; KRASwt = KRAS wild-type; QW = every week; 
Q2W = every 2 weeks. 
a 
Cetuximab is given on a weekly schedule. 
b 
A loading dose of 5F9 at 45 mg/kg is given on Day 11. 
 


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1.2 
Study Objectives and Endpoints 
PRIMARY 
OBJECTIVES 
ENDPOINTS 
• 
To investigate the safety and tolerability, and 
to determine the RP2DS for 5F9 in 
combination with cetuximab. 
• 
To evaluate objective response rate (ORR)  
of 5F9 in combination with cetuximab in 
patients with KRAS mutant and KRAS     
wild-type CRC according to Response 
Evaluation Criteria in Solid Tumors 
(RECIST) v 1.1 (Eisenhauer 2009). 
• 
DLTs and adverse events (AEs) according to 
National Cancer Institute Common 
Terminology Criteria for Adverse Events 
(NCI CTCAE) v 4.03. 
• 
ORR using complete response (CR) + partial 
response (PR) as defined by the investigator 
according to RECIST v 1.1. 
SECONDARY 
OBJECTIVES 
ENDPOINTS 
• 
To evaluate the pharmacokinetic (PK)  
profile of 5F9 in combination with 
cetuximab. 
• 
To evaluate the immunogenicity of 5F9 in 
combination with cetuximab. 
• 
To evaluate efficacy of 5F9 in combination 
with cetuximab by the disease-control rate 
(DCR), duration of response (DOR), 
progression-free survival (PFS), overall 
survival (OS), and time to progression (TTP) 
for patients with KRAS mutant and KRAS 
wild-type CRC according to RECIST v 1.1 
(Eisenhauer 2009). 
• 
To evaluate the ORR of 5F9 in combination 
with cetuximab in patients with KRAS 
mutant and KRAS wild-type CRC according 
to iRECIST guidelines (Seymour 2017). 
• 
5F9 concentration versus time measurements 
of 5F9 in combination with cetuximab. 
• 
Antidrug antibodies to 5F9 and cetuximab. 
• 
DCR, DOR, PFS, OS, and TTP as defined by 
the investigator according to RECIST v 1.1. 
• 
ORR using iCR + iPR as defined by the 
investigator according to the iRECIST 
guidelines. 
 


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1.3 
Sample Size Determination 
Depending on dose escalation and expansion, an estimated number of 15 to 24 patients will be 
enrolled in Phase 1b, and 88 patients will be enrolled in Phase 2. 
No formal hypothesis testing will be done.  In Phase 2, it is planned to enroll an expansion cohort 
of 44 patients with KRAS mutant CRC and another expansion cohort of 44 patients with KRAS 
wild-type CRC.  This sample size was determined using a one-sided alpha level of 0.10 and a 
power of 80% based on a null hypothesis of 5% response rate compared with an alternative 
hypothesis of 15% for each cohort. 
2 
ANALYSIS SETS 
• All Treated Patients:  includes all patients who receive at least 1 dose of any study drugs.  
Summary tables of disposition, demographics and other baseline characteristics, efficacy, 
and safety analyses will be performed on the All Treated Patients. 
• DLT Evaluable Analysis Set:  includes patients who received at least 1 dose of any study 
drugs during Phase 1b if the patient either experienced a DLT any time during the DLT 
Assessment Period (the first 4 weeks of treatment) or completed at least 4 infusions of 5F9 
and 2 infusions of cetuximab.  Patients who withdraw before completing the 4-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.  
The same definition is applicable to the Phase 2 Safety Run-In to identify the first 9 DLT 
Evaluable Patients. 
• PK Analysis Set:  patients who receive any amount of magrolimab with at least one 
detectable post-treatment serum concentration of magrolimab are evaluable for PK 
analysis. 
• Immunogenicity Analysis Set:  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 efficacy will be 
presented for All Treated Patients. 
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 


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for discontinuation, duration of treatment (months), and duration of follow up (months).  The 
summaries will be provided for each dosing cohort (Phase 1b) or each expansion cohort (Phase 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, and 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 01 Mar 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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3.7 
Premedication 
Premedication is required before administration of the first cetuximab dose and before the first 
2 doses of 5F9 (inclusive of the priming dose).  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 doses of 5F9 (inclusive of the 
priming dose)  
• H1 antagonist (eg, 50 mg of diphenhydramine) intravenously and other agents (ie, 
glucocorticoids, etc.) on the date of but prior to the first cetuximab dose 
 
3.8 
Subsequent Lines of Anticancer Therapy 
Subsequent therapies received after the last dose of study treatment will be summarized by WHO 
ATC class and preferred names.  Each patient will be counted once for each preferred name, and 
each ATC class. 
4 
EFFICACY ANALYSIS 
Confirmed best response based on RECIST v1.1 will be summarized for All Treated Patients with 
CRC by cohort for KRAS wild-type and KRAS mutant patients separately. ORR will be calculated 
based on All Treated Patients with measurable disease at baseline. 
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.  Patients who do not have objectively 
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 for All Treated Patients with CRC by cohort for KRAS 
wild-type and KRAS mutant patients separately.   
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 


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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-5F9 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 5F9 maintenance dose level based on the All 
Treated Patients. 
6.1 
Extent of Exposure 
Exposure to study treatment will be summarized in each cohort for the All Treated Patients.  
Descriptive statistics will be provided for the following data for each study drugs (5F9, 
Cetuximab): 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.   
6.2 
Adverse Events 
Treatment-emergent adverse events (TEAE) will be summarized in each cohort.  Summaries will 
be restricted to 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 6.1.5.2.1) severity scoring. 
The following summaries will be presented: 
PPD


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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 DLTs and the average number of 
infusions in these patients will be tabulated. 
Listings of all AEs including TEAEs, TEAEs related to either 5F9 or cetuximab, 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. 
6.3 
Deaths 
All deaths and causes of death on study will be summarized and listed. 
6.4 
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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6.5 
Vital Signs 
Vital sign measurement results will only be provided in a data listing. 
6.6 
Physical Examination 
Physical examination results will only be provided in a data listing. 
6.7 
Electrocardiogram 
Electrocardiogram results will only be provided in a data listing. 
6.8 
Peripheral Blood Smear 
Peripheral blood smear parameters will be summarized using frequency counts with percentages 
at each time point.  
6.9 
Visual Acuity and Retinal Imaging 
Visual acuity and retinal imaging data will only be provided in a data listing. 
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 was 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. 
• Endpoint TTP will not be summarized. 
• The tumor assessment based on iRECIST will not be reported. 
• All enrolled patients received at least 1 dose of 5F9.  Enrolled Analysis Set, Efficacy 
Analysis Set, and Safety Analysis Set are consolidated into All Treated Patients for all 
efficacy and safety analyses.  Per-Protocol Analysis Set is not defined any more. 
 
8 
REFERENCES 
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. 
Seymour L, Bogaerts J, Perrone A, et al. RECIST working group. iRECIST: Guidelines for 
response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 2017 
Mar;18(3):e143-e152.