Clinical trial NCT03422627
Conditions: Chronic Graft Versus Host Disease cGVHD
Sponsor: Amgen
Start date: 2018-04-27; Completion date: 2022-10-13
Enrollment: 32 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
Phase 1b: To evaluate the safety and tolerability of multiple ascending doses of efavaleukin alfa in subjects with steroid refractory chronic graft versus host disease (cGVHD).

Phase 2: To evaluate the efficacy of efavaleukin alfa in subjects with steroid refractory cGVHD as measured by overall response rate (ORR) at 16 weeks according to the 2014 cGVHD NIH Consensus Criteria.

Due to early termination, the Phase 2 portion of this study was not conducted.

Detailed description:

Arms: arm 1: Efavaleukin will be administered as multiple ascending doses (MAD) across cohorts 1-5. Each dosing cohort will consist of between 3 and 6 subjects who will receive efavaleukin alfa subcutaneously (SC) either every week or every 2 weeks plus protocol permitted background therapy for 52 weeks. At the discretion of the Sponsor, following discussion and agreement between the principal investigator and medical monitor, subjects responding to efavaleukin alfa (as assessed by the end of week 50), who wish to continue treatment, may continue to receive efavaleukin alfa treatment at their current dosing regimen. arm 2: The phase 2 portion of this study will be conducted as a single arm, multi-center, open label trial in subjects with steroid refractory chronic graft versus Host Disease (cGVHD). All subjects will receive the recommended phase 2 dose (RP2D) of efavaleukin alfa for up to 52 weeks plus protocol permitted background therapy for cGVHD.

Due to early study termination the Phase 2 portion of the study was never opened.
Interventions: intervention 1: Efavaleukin Alfa
Intervention descriptions: intervention 1: Phase 1: This study will be conducted as a multiple ascending dose (MAD) study. Each dosing cohort will consist of between 3 and 6 subjects who will receive efavaleukin alfa subcutaneously (SC) either every week or every 2 weeks plus protocol permitted background therapy for 52 weeks. At the discretion of the Sponsor, following discussion and agreement between the principal investigator and medical monitor, subjects responding to efavaleukin alfa (as assessed by the end of week 50), who wish to continue treatment, may continue to receive efavaleukin alfa treatment at their current dosing regimen for up to an additional 208 weeks through an extended dosing period. All subjects who continue to receive efavaleukin alfa during the extended dosing period will be reevaluated every 6 months for their response to treatment.

Phase 2: All subjects will receive the recommended phase 2 dose (RP2D) of efavaleukin alfa for 52 weeks.

Protocol documents:
Prot_000.pdf: 
Product:  Efavaleukin Alfa 
Protocol Number:  20160283 
Date:  22 June 2021 
Page 1 of 148 
 
Title Page 
Protocol Title: 
A Phase 1b/2 Open-label Study Evaluating 
the Safety, Tolerability, Pharmacokinetics, 
Pharmacodynamics, and Efficacy of 
Efavaleukin Alfa in Adult Subjects With 
Steroid Refractory Chronic Graft Versus Host 
Disease 
Short Protocol Title: 
Safety and Efficacy of Efavaleukin Alfa in 
Subjects With Steroid Refractory Chronic 
Graft versus Host Disease 
Protocol Number: 
20160283 
Investigational Product: 
Efavaleukin Alfa 
Trade Name: 
Not applicable 
Sponsor Name of Sponsor: 
Amgen Inc. 
Address: 
One Amgen Center Drive, Thousand Oaks, 
CA, 91320, USA 
Telephone Number: +1-805-447-1000 
Key 
Sponsor 
Contact 
Name: 
 MD 
Address: 
One Amgen Center Drive 
Thousand Oaks, CA 91320-1799 
Telephone Number: 
Email Address: 
EudraCT Number: 
2017-000763-33 
NCT Number: 
NCT03422627 
Protocol Date: 
Document Version 
Date 
Original 
13 April 2017 
Amendment 1 
22 August 2017 
Amendment 2 
04 December 2018 
Amendment 3 
26 August 2019 
Amendment 4 
08 December 2020 
Amendment 5 
22 June 2021 
Version/Date: 
Data Element 
Standards Version 
Date 
5.0 
20 March 2015 
 


Product:  Efavaleukin Alfa 
Protocol Number:  20160283 
Date:  22 June 2021 
Page 2 of 148 
 
Confidentiality Notice 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics 
committee/institutional scientific review board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent 
of Amgen Inc. 
If you have questions regarding how this document may be used or shared, call 
the Amgen Medical Information number:  US sites, 1- 800-77-AMGEN; Canadian 
sites, 1-866-50-AMGEN; Amgen’s general number in the US, 1-805-447-1000. 


Product:  Efavaleukin Alfa 
Protocol Number:  20160283 
Date:  22 June 2021 
Page 3 of 148 
 
Investigator's Agreement 
I have read the attached protocol entitled A Phase 1b/2 Open-label Study Evaluating the 
Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of Efavaleukin 
Alfa in Adult Subjects With Steroid Refractory Chronic Graft Versus Host Disease, 
dated 22 June 2021, and agree to abide by all provisions set forth therein.   
I agree to comply with the International Council for Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP), Declaration of Helsinki, and applicable 
national or regional regulations/guidelines. 
I agree to ensure that Financial Disclosure Statements will be completed by:  me 
(including, if applicable, my spouse or legal partner and dependent children) and my 
subinvestigators (including, if applicable, their spouses or legal partners and dependent 
children) at the start of the study and for up to 1 year after the study is completed, if 
there are changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc. 
 
_______________________________ 
Signature 
 
_______________________________ 
____________________________ 
Name of Investigator  
 
 
 
Date (DD Month YYYY) 


Product:  Efavaleukin Alfa 
Protocol Number:  20160283 
Date:  22 June 2021 
Page 4 of 148 
 
Table of Contents 
1. 
Protocol Synopsis ................................................................................................. 10 
2. 
Study Schema and Schedule of Activities ............................................................. 17 
2.1 
Study Schema ........................................................................................... 17 
2.2 
Schedule of Activities ................................................................................ 20 
3. 
Introduction ........................................................................................................... 48 
3.1 
Study Rationale ......................................................................................... 48 
3.2 
Background ............................................................................................... 48 
3.2.1 
Disease ..................................................................................... 48 
3.2.2 
Amgen Investigational Product Background:  
Efavaleukin Alfa ........................................................................ 50 
3.2.2.1 
Toxicology ............................................................... 50 
3.2.2.2 
Human Exposure .................................................... 51 
3.2.2.3 
Clinical Experience .................................................. 52 
3.2.3 
Risk Assessment ....................................................................... 52 
3.2.4 
Experience With Other Similar Biological Agents ....................... 53 
4. 
Objectives, Endpoints and Hypotheses ................................................................. 54 
4.1 
Objectives and Endpoints .......................................................................... 54 
4.2 
Hypotheses ............................................................................................... 57 
5. 
Study Design ........................................................................................................ 57 
5.1 
Overall Design .......................................................................................... 57 
5.1.1 
Phase 1b ................................................................................... 57 
5.2 
Number of Subjects ................................................................................... 60 
5.2.1 
Replacement of Subjects ........................................................... 61 
5.2.2 
Number of Sites ......................................................................... 61 
5.3 
End of Study ............................................................................................. 61 
5.3.1 
End of Study Definition .............................................................. 61 
5.3.2 
Study Duration for Subjects ....................................................... 61 
5.4 
Justification for Investigational Product Dose ............................................ 62 
6. 
Study Population .................................................................................................. 63 
6.1 
Inclusion Criteria ....................................................................................... 63 
6.2 
Exclusion Criteria ...................................................................................... 65 
6.3 
Lifestyle Restrictions ................................................................................. 67 
6.3.1 
Alcohol and Tobacco (Phase 1b) ............................................... 67 
6.4 
Subject Enrollment .................................................................................... 68 
6.5 
Screen Failures ......................................................................................... 68 
7. 
Treatments ........................................................................................................... 68 
7.1 
Treatment Procedures............................................................................... 69 


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Date:  22 June 2021 
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7.1.1 
Investigational Products ............................................................ 69 
7.1.2 
Non-investigational Products ..................................................... 70 
7.1.3 
Medical Devices ........................................................................ 70 
7.1.4 
Other Protocol-required Therapies ............................................ 70 
7.1.5 
Other Treatment Procedures ..................................................... 70 
7.1.6 
Product Complaints ................................................................... 70 
7.1.7 
Excluded Treatments, Medical Devices, and/or 
Procedures During Study Period ............................................... 70 
7.2 
Method of Treatment Assignment ............................................................. 71 
7.3 
Blinding ..................................................................................................... 71 
7.4 
Dose Modification ...................................................................................... 71 
7.4.1 
Phase 1b Dose-cohort Study Escalation/De-escalation ............. 71 
7.4.1.1 
Dose Level Review Meetings .................................. 71 
7.4.1.2 
Definition of Dose Limiting Toxicities for 
Phase 1b ................................................................. 71 
7.4.2 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ..................................... 72 
7.4.2.1 
Amgen Investigational Product:  
Efavaleukin Alfa ...................................................... 72 
7.4.3 
Hepatotoxicity Stopping and Rechallenge Rules ....................... 74 
7.5 
Preparation/Handling/Storage/Accountability ............................................ 74 
7.6 
Treatment Compliance .............................................................................. 74 
7.7 
Treatment of Overdose ............................................................................. 74 
7.8 
Prior and Concomitant Treatment ............................................................. 75 
7.8.1 
Prior Treatment ......................................................................... 75 
7.8.2 
Concomitant Treatment ............................................................. 75 
7.8.2.1 
Corticosteroids ........................................................ 75 
7.8.2.2 
Other Immunosuppressive Medications ................... 76 
7.8.2.3 
Prophylaxis for Infection .......................................... 76 
7.8.2.4 
Other Allowed Therapies ......................................... 76 
8. 
Discontinuation Criteria ......................................................................................... 76 
8.1 
Discontinuation of Study Treatment........................................................... 77 
8.2 
Discontinuation From the Study ................................................................ 77 
8.2.1 
Reasons for Removal From Washout, Run-in or 
Invasive Procedures .................................................................. 78 
8.2.2 
Reasons for Removal From Study ............................................. 78 
8.3 
Lost to Follow-up ....................................................................................... 78 
9. 
Study Assessments and Procedures .................................................................... 80 
9.1 
General Study Periods .............................................................................. 80 
9.1.1 
Screening, Enrollment and/or Randomization ............................ 80 
9.1.2 
Treatment Period ....................................................................... 81 
9.1.3 
Progressive Disease Visit .......................................................... 81 


Product:  Efavaleukin Alfa 
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9.1.4 
End of Treatment ....................................................................... 81 
9.1.5 
Safety Follow-up/End of Study .................................................. 82 
9.2 
Description of General Study Assessments and Procedures ..................... 82 
9.2.1 
General Assessments ............................................................... 82 
9.2.1.1 
Informed Consent .................................................... 82 
9.2.1.2 
Demographics ......................................................... 82 
9.2.1.3 
Medical History ........................................................ 83 
9.2.1.4 
GVHD Staging Evaluation ....................................... 83 
9.2.1.5 
Physical Examination .............................................. 83 
9.2.1.6 
Physical Measurements .......................................... 83 
9.2.1.7 
Substance Abuse History ........................................ 83 
9.2.2 
Efficacy Assessments ................................................................ 83 
9.2.2.1 
Response Assessment:  NIH cGVHD 
Response Assessment  (NIH Form A) ..................... 83 
9.2.3 
Safety Assessments .................................................................. 87 
9.2.3.1 
Adverse Events and Serious Adverse 
Events ..................................................................... 87 
9.2.3.2 
Vital Signs ............................................................... 90 
9.2.3.3 
Electrocardiograms (ECGs) ..................................... 90 
9.2.4 
Clinical Laboratory Assessments ............................................... 90 
9.2.4.1 
Human Immunodeficiency Virus (HIV) 
Status ...................................................................... 91 
9.2.4.2 
Hepatitis B and C Status ......................................... 91 
9.2.4.3 
Tuberculosis Testing ............................................... 91 
9.2.4.4 
Pregnancy Testing .................................................. 93 
9.2.4.5 
Prespecified Biomarker Assessments ..................... 93 
9.2.5 
Pharmacokinetic Assessments .................................................. 93 
9.2.6 
Pharmacodynamic Assessments ............................................... 94 
9.2.7 
Pharmacogenetic Assessments................................................. 94 
9.2.8 
Antibody Testing Procedures ..................................................... 94 
9.2.9 
Biomarker Development ............................................................ 95 
9.2.10 
Clinical Outcome Assessments ................................................. 95 
9.2.11 
Other Assessments ................................................................... 96 
9.2.11.1 
Peripheral Blood Mononuclear Cell ......................... 96 
9.2.11.2 
Hospitalizations ....................................................... 96 
10. 
Statistical Considerations ...................................................................................... 96 
10.1 
Sample Size Determination ....................................................................... 96 
10.1.1 
Phase 1b ................................................................................... 96 


Product:  Efavaleukin Alfa 
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Date:  22 June 2021 
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10.2 
Analysis Sets, Subgroups, and Covariates ................................................ 97 
10.2.1 
Analysis Sets ............................................................................. 97 
10.2.2 
Covariates ................................................................................. 98 
10.2.3 
Subgroups ................................................................................. 98 
10.2.4 
Handling of Missing and Incomplete Data .................................. 98 
10.3 
Adaptive Design ........................................................................................ 98 
10.4 
Statistical Analyses ................................................................................... 98 
10.4.1 
Planned Analyses ...................................................................... 98 
10.4.1.1 
Interim Analysis and Early Stopping 
Guidelines ............................................................... 98 
10.4.1.3 
Final Analysis .......................................................... 99 
10.4.2 
Methods of Analyses ................................................................. 99 
10.4.2.1 
General Considerations ........................................... 99 
10.4.2.2 
Efficacy Analyses .................................................. 101 
10.4.2.3 
Safety Analyses .................................................... 102 
10.4.2.4 
Other Analyses ...................................................... 103 
11. 
References ......................................................................................................... 104 
12. 
Appendices ......................................................................................................... 106 
Appendix 1.  List of Abbreviations and Definitions of Terms ................................ 107 
Appendix 2.  Clinical Laboratory Tests ................................................................ 112 
Appendix 3.  Study Governance Considerations ................................................. 114 
Dose Level Review Meetings .................................................................. 114 
Dose Level Determination ....................................................................... 115 
Regulatory and Ethical Considerations .................................................... 115 
Informed Consent Process ...................................................................... 116 
Data Protection/Subject Confidentiality ................................................... 118 
Publication Policy .................................................................................... 118 
Investigator Signatory Obligations ........................................................... 119 
Data Quality Assurance ........................................................................... 120 
Source Documents .................................................................................. 121 
Study and Site Closure............................................................................ 122 
Compensation ......................................................................................... 122 
Appendix 4.  Safety Events:  Definitions and Procedures for Recording, 
Evaluating, Follow-up and Reporting ....................................................... 123 
Definition of Disease-related Event ......................................................... 123 
Definition of Adverse Event ..................................................................... 123 
Definition of Serious Adverse Event ........................................................ 125 
Recording Adverse Events, Disease-related Events 
(if applicable), and Serious Adverse Events ............................ 125 
Evaluating Adverse Events and Serious Adverse Events ........................ 127 


Product:  Efavaleukin Alfa 
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Reporting of Serious Adverse Event ........................................................ 128 
Appendix 5.  Contraceptive Guidance and Collection of Pregnancy and 
Lactation Information ............................................................................... 132 
Definition of Females of Childbearing Potential ....................................... 132 
Collection of Pregnancy Information ........................................................ 133 
Collection of Lactation Information .......................................................... 134 
Appendix 6.  Sample Storage and Destruction .................................................... 137 
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions and 
Follow-up Assessments and Study Treatment Rechallenge 
Guidelines ............................................................................................... 139 
Criteria for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other 
Protocol-required Therapies Due to Potential 
Hepatotoxicity.......................................................................... 139 
Criteria for Rechallenge of Amgen Investigational Product and 
Other Protocol-required Therapies After Potential 
Hepatotoxicity.......................................................................... 140 
Drug-induced Liver Injury Reporting and Additional 
Assessments ........................................................................... 141 
Appendix 8.  NIH Defined Diagnostic or Distinctive Features of Chronic 
GVHD ..................................................................................................... 143 
Appendix 9.  NIH Global Severity of cGVHD ....................................................... 146 
Appendix 11.  Disease Related Events Table ..................................................... 148 
 
List of Tables 
Table 2-1.  Phase 1b Schedule of Activities – Screening Through Week 5 .................... 20 
Table 2-2.  Phase 1b Schedule of Activities – Week 6 Through Week 52 ...................... 24 
Table 2-3.  Phase 1b Schedule of Activities – Extended Dosing Period 
Subjects Only (Week 53 Through Week 104) ......................................... 28 
Table 2-4.  Phase 1b Schedule of Activities – Extended Dosing Period 
Subjects Only (Week 105 Through Week 158) ....................................... 31 
Table 2-5.  Phase 1b Schedule of Activities – Extended Dosing Period 
Subjects Only (Week 159 Through Week 222) ....................................... 34 
Table 2-6.  Phase 1b Schedule of Activities – Extended Dosing Period 
Subjects Only (Week 223 Through Week 260) ....................................... 37 


Product:  Efavaleukin Alfa 
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Date:  22 June 2021 
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Table 3-1.  Predicted Efavaleukin Alfa Steady State Exposures After 
16 Weekly Subcutaneous Administrations of Efavaleukin Alfa 
in cGVHD Subjects for the Proposed Doses and Margins 
Relative to the 3-month GLP Repeat-dose Cynomolgus 
Monkey Exposure at the NOAEL of 30 g/kg 
(Study 20160283) ................................................................................... 52 
............. 63 
............. 63 
Table 7-1.  Study Treatments ........................................................................................ 69 
Table 12-1.  Analyte Listing ......................................................................................... 113 
Table 12-2.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity ............................................ 140 
List of Figures 
Figure 2-1.  Study Schema Phase 1b ............................................................................ 17 
Figure 12-1.  Sample Electronic Serious Adverse Event Contingency Form ................ 129 
Figure 12-2.  Pregnancy and Lactation Notification Worksheet .................................... 135 


Product:  Efavaleukin Alfa 
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1. 
Protocol Synopsis 
Protocol Title:  A Phase 1b/2 Open-label Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics, and Efficacy of Efavaleukin Alfa in Adult 
Subjects With Steroid Refractory Chronic Graft Versus Host Disease 
Short Protocol Title:  Safety and Efficacy of Efavaleukin Alfa in Subjects With Steroid 
Refractory Chronic Graft versus Host Disease 
Study Phase:  1b/2 
Indication:  Chronic graft versus host disease (cGVHD) 
Rationale 
This is an open-label, phase 1b/2 study to evaluate the safety and efficacy of efavaleukin 
alfa (AMG 592) in subjects with steroid refractory cGVHD.  The phase 1b part of the 
study will evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of 
efavaleukin alfa and will define the maximum tolerated dose (MTD) and/or a biologically 
optimal dose.
Objective(s)/Endpoint(s) 
 
Objectives 
Endpoints 
Primary 
Phase 1b 
 
To evaluate the safety and tolerability of 
multiple ascending doses of efavaleukin 
alfa in subjects with steroid refractory 
cGVHD in order to estimate the MTD 
 
 
Phase 1b 
 
Incidence of dose limiting toxicities (DLTs) 
at first 4 weeks 
 
Incidence of all treatment-related and 
treatment-emergent adverse events and 
serious adverse event 
Secondary 


Product:  Efavaleukin Alfa 
Protocol Number:  20160283 
Date:  22 June 2021 
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Objectives 
Endpoints 
Secondary (continued) 
 


Product:  Efavaleukin Alfa 
Protocol Number:  20160283 
Date:  22 June 2021 
Page 12 of 148 
 
Hypotheses 
Phase 1b 
Efavaleukin alfa will be safe and well-tolerated in subjects with steroid refractory cGVHD. 
Overall Design 
This is an open-label, multi-center, phase 1b/2 study to evaluate the safety and efficacy 
of efavaleukin alfa in subjects with steroid refractory cGVHD.  The study will be 
conducted in 2 portions as described below. 
Phase 1b 
The phase 1b part of this study will be conducted as a multiple ascending dose (MAD) 
study.  Each dosing cohort will consist of between 3 and 6 DLT-evaluable subjects who 
will receive efavaleukin alfa SC either every week (QW) or every 2 weeks (Q2W) plus 
protocol permitted background therapy for 52 weeks.  The DLT evaluation period is 
defined as 4 weeks after the first dose of study drug.  At the discretion of the Sponsor, 
following discussion and agreement between the principal investigator and medical 
monitor, subjects responding to efavaleukin alfa (as assessed by the end of week 50), 
who wish to continue treatment, may continue to receive efavaleukin alfa treatment at 
their current dosing regimen for up to an additional 52 weeks.  The remaining subjects 
will complete the week 52/EOT visit.  All subjects who continue to receive efavaleukin 
alfa during the extended dosing period will be reevaluated at week 76 for their response 
to treatment.  Following discussion and agreement between the principal investigator 
and medical monitor, the Sponsor may decide to allow these subjects to continue 
treatment through week 102 (Q2W dose) or week 103 (QW dose).  Subjects 
participating in extended dosing through week 104 will complete the week 104/end of 
extended treatment (EOET) visit (see Table 2-3).  At the discretion of the Sponsor, 
following discussion and agreement between the principal investigator and 
medical monitor, subjects responding to efavaleukin alfa (as assessed by the end 
of week 104), who wish to continue treatment beyond week 104, may continue to 
receive efavaleukin alfa treatment at their current dosing regimen for up to an 
additional 156 weeks.  Only subjects who are deemed eligible to continue 
extended dosing beyond week 102 or week 103 will complete dosing at week 104.  
The remaining subjects will complete the week 104/EOET visit.  All subjects who 
continue to receive efavaleukin alfa during the extended dosing period will be 
reevaluated every 6 months for their response to treatment.  Following discussion 
and agreement between the principal investigator and medical monitor, the 
Sponsor may decide to allow these subjects to continue treatment through 
week 258 (Q2W dose) or week 259 (QW dose).  Subjects participating in extended 
dosing through week 258 or 259 will complete the week 260/EOET visit (see 
Table 2-6).  All subjects will complete the 6-week safety follow-up after the last dose of 
efavaleukin alfa. 
Five dose levels are planned:  
 µg Q2W (cohort 1a), 
 µg QW (cohort 2a), 
 µg 
Q2W (cohort 3), 
 µg QW (cohort 4), and 
 µg Q2W (cohort 5).  Dose levels 1a 
(
 µg Q2W) and 2a (
 µg QW) will be enrolled concurrently.  Three subjects each 
will be assigned to cohorts 1a (
 µg Q2W) and 2a (
 µg QW) alternately (total of 


Product:  Efavaleukin Alfa 
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6 subjects).  After the last subject completes the DLT evaluation period, a dose level 
review meeting (DLRM) will occur and if deemed necessary, 3 additional subjects each 
will be assigned to cohorts 1a and 2a alternately (total of 6 subjects) to gain additional 
information.  After the last subject completes the DLT evaluation period, a DLRM will 
occur and if dose escalation is deemed appropriate, subjects will be enrolled in cohorts 3 
(
 µg Q2W), 4 (
 µg QW), and 5 (
 µg Q2W) as follows:  first, 3 subjects will 
be enrolled in cohort 3.  An internal safety review will be conducted by the Amgen 
Medical Monitor and Global Safety Officer after the first 3 subjects complete the DLT 
evaluation period.  If concerning safety issues are identified, a DLRM will occur to 
assess if it is safe to proceed with additional enrollment in cohort 3 and concurrent 
enrollment in cohort 4.  If no concerning safety issues are identified in these first 3 
subjects, enrollment of the remaining 3 subjects in cohort 3 will proceed without a 
DLRM.  Concurrently, enrollment of 6 subjects in cohort 4 will begin with alternate 
assignment of subjects between cohorts 3 and 4 until enrollment of cohort 3 has 
completed.  Enrollment of 6 subjects in cohort 5 will begin after the DLRM for cohort 4 is 
complete.  DLRMs for cohorts 3, 4, and 5 will occur after the last subject in that cohort 
completes the DLT evaluation period. 
All planned dose levels for a given cohort may be adjusted at any time based on 
emerging data.  Additional dosing cohorts may be added, removed, or substituted at any 
time based on emerging data and the results of continuous modelling. 
After there is at least 1 DLT observed at any dose level, a Bayesian logistic regression 
model (BLRM) (Bailey et al, 2009; Neuenschwander et al, 2008) will be used to inform 
dose escalation and the results of this analysis will be provided to the DLRM.  
Three toxicity probability intervals (TPI) of DLT will be defined:  target TPI (20% to 30%), 
excessive TPI (30% to 60%), and unacceptable TPI (60% to 100%).  Adverse events 
meeting DLT criteria after week 4 and PD information may also be included in the model, 
as available.  The model will recommend an MTD as the dose with the highest 
probability in the target TPI, but with less than 25% probability in excessive TPI and 
unacceptable TPI.  Lower dose levels, intermediate dose levels, or alternative dosing 
schedules may be considered based on all available information as long as they do not 
exceed the estimated MTD per the model.  In addition, Amgen may add subjects to dose 
levels below the MTD in order to better characterize PK and PD.  After DLT is observed, 
the BLRM model will be run after each dosing cohort and may be run at any time to 
continuously update the MTD information.  For technical details of BLRM, please refer to 
the statistical analysis plan (SAP). 
During or after completion of the dose escalation part of the study, Amgen may enroll 
approximately 10 subjects in an optional dose expansion cohort in order to gain 
additional safety and efficacy information prior to the selection of an 
.  
Determination of the dose for the dose expansion cohort will be based on review of all 
available information, including but not limited to BLRM model, other safety data, PK/PD, 
and efficacy.  This dose cannot exceed the model predicted MTD.  A dose that has not 
been previously explored may also be considered.  The BLRM model may be run 
anytime during the dose expansion cohort, and Amgen may change the expansion 
cohort dose level or add additional subjects for dose expansion based on emerging 
information. 
After all subjects in the phase 1b part of the study have had the opportunity to undergo 
assessment for the week 16 visit Amgen will review all the available information, 
including but not limited to the BLRM model, other safety data, PK/PD, and efficacy, to 
select the 
. 


Product:  Efavaleukin Alfa 
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All phase 1b subjects will continue efavaleukin alfa treatment at their current dose until 
the 
 is established.  Subjects still receiving or planned to receive efavaleukin alfa 
treatment at the time that the 
 is established may change their efavaleukin alfa 
dose to the 
 dose at the discretion of the Sponsor, following discussion and 
agreement between the principal investigator and medical monitor, and may continue 
study treatment through the week 260/EOET visit if they remain eligible for extended 
dosing (see Table 2-6). 
Number of Subjects 
Approximately 40 subjects will be enrolled in phase 1b of the study, with about 
30 subjects in the dose escalation cohorts and approximately 10 subjects in the optional 
dose expansion cohort.  The total sample size may be higher than 40 subjects if, 
following a DLRM recommendation or Amgen decision to evaluate additional doses, 
dosing cohorts are added and/or existing cohorts are expanded; or subjects are replaced 
as per Section 5.2.1.  Additional subjects may be enrolled in each cohort to enable all 
screened eligible subjects to participate in the study. 
 
Summary of Subject Eligibility Criteria 
The study will enroll subjects who are recipients of an allogeneic hematopoietic stem cell 
transplant (HSCT), have been diagnosed with moderate to severe steroid-refractory 
cGVHD per the 2014 cGVHD NIH Consensus Criteria, have received no more than 
3 previous treatments for cGVHD (excluding topical agents), have a Karnofsky 
performance status score ≥ 50%, have adequate renal, cardiac and bone marrow 
function, have adequate hepatic and pulmonary function (unless related to cGVHD), and 
an estimated life expectancy of greater than 3 months.  Subjects who are receiving 
systemic corticosteroids at baseline must be on a stable corticosteroid dose from 
2 weeks prior to the first dose of efavaleukin alfa and must have an ongoing systemic 
prednisone requirement ≤ 1 mg/kg/day (or equivalent).  Subjects who are receiving 
non-corticosteroid immunosuppressants at baseline must be on a stable dose from 
2 weeks prior to the first dose of efavaleukin alfa.  Subjects will be excluded from the 
study if they have active morphologic relapse/progression of hematologic malignancy 
post transplantation, received a donor lymphocyte infusion T-cell depleting, B-cell 
depleting or IL-2 signaling targeted medication within 12 weeks prior to starting 
efavaleukin alfa, received T regulatory cell expanding therapies, ibrutinib, imatinib, 
bortezomib, entospletinib, ruxolitinib or other JAK inhibitor, or an investigational drug or 


Product:  Efavaleukin Alfa 
Protocol Number:  20160283 
Date:  22 June 2021 
Page 15 of 148 
 
device within 4 weeks prior to starting efavaleukin alfa, or have a known history of active 
tuberculosis. 
For a full list of eligibility criteria, please refer to Section 6.1 to Section 6.2. 
Treatments 
Subjects will receive a SC dose of efavaleukin alfa QW or Q2W starting on day 1 until 
week 50 (Q2W dose) or 51 (QW dose).  Subjects in phase 1b may continue to receive 
efavaleukin alfa at their current dosing regimen (QW or Q2W) for up to an additional 
208 weeks (through week 258 or week 259, respectively) at the discretion of the 
Sponsor, following discussion and agreement between the principal investigator and 
medical monitor. 
Efavaleukin alfa will be provided in glass vials. 
Efavaleukin alfa will be stored between 2°C and 8°C.  All doses will be fixed, and the 
qualified site personnel will prepare the appropriate dose for each subject. 
Procedures 
Written informed consent must be obtained from all subjects before any study‑specific 
screening procedures are performed.  Among the procedures performed, blood samples 
will be collected from subjects for serum chemistry, hematology, PK samples, 
, lymphocyte subsets, biomarker development, optional 
pharmacogenetic sample, and PBMC. 
All subjects in the study will have their disease response assessed using the NIH 
cGVHD Response assessment (NIH Form A).  
 
 
Safety assessments including adverse events, serious adverse events, and 
disease-related events assessments will be performed throughout the duration of the 
study. 
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 9.2 and the Schedule of Activities in Table 2-1, Table 2-2, Table 2-3, Table 2-4, 
Table 2-5, Table 2-6, Table 2-7, and Table 2-8. 
Statistical Considerations 
The baseline demographics, disease characteristics, and the exposure to efavaleukin 
alfa by dose level will be summarized using descriptive statistics.  Summary descriptive 
statistics by dose level group will be provided.  For categorical endpoints, the descriptive 
statistics will contain the frequency and percentage.  For continuous endpoints, the 
descriptive statistics will include the number of observations, mean, standard deviation, 
median, minimum, and maximum.  
Statistical testing will be performed with statistical significance level of 0.025 for 1-sided 
tests, and with 0.05 statistical significance level for 2-sided tests, unless specified 
otherwise.  No multiplicity adjustment will be provided, unless specified otherwise. 
Primary Efficacy Endpoint  


Product:  Efavaleukin Alfa 
Protocol Number:  20160283 
Date:  22 June 2021 
Page 16 of 148 
Secondary Endpoints 
Safety Endpoints: 
The Medical Dictionary for Regulatory Activities (MedDRA version 20.0 or later) will be 
used to code all adverse events to a system organ class and a preferred term.  Subject 
incidence of all treatment-emergent adverse events will be tabulated by system organ 
class and preferred term.  Tables of fatal adverse events, serious adverse events, and 
adverse events leading to withdrawal from investigational product or other 
protocol-required therapies will also be provided.  In addition, summary statistics and 
shifts in grades of selected safety laboratory values and summary statistics for vital signs 
will be provided. 
The incidence and percentage of subjects who develop 
 
 at any time will be tabulated by dose level.  The 
incidence and percentage of subjects who develop
 
 will also be 
tabulated. 
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor Name:  Amgen Inc. 


Product:  Efavaleukin Alfa 
Protocol Number:  20160283 
Date: 22 June 2021 
Page 17 of 148 
 
CONFIDENTIAL 
Version 15.1, 14 Apr 2017 
 
2. 
Study Schema and Schedule of Activities 
2.1 
Study Schema 
Figure 2-1.  Study Schema Phase 1b 
Cohort 1a:  
µg Q2W (N = 3):  52 weeksc
SFU/EOS:  6 weeks
DLRM
Cohort X, Y…:  xx, y y, µga
Additional Dosing Cohorts may  be added 
or remov ed af ter completion of  
Cohorts 1a/2ab:  52 weeksc
SFU/EOS
6 weeks
DLRM
Optional dose expansion cohort:  up to N = 10:  52 weeksc
SFU/EOS:  6 weeks
Cohort 2a:  
µg QW (N = 3):  52 weeksc
SFU/EOS:  6 weeks
Cohort 1a expansion:  
µg Q2W (N = 3):  52 weeksc
SFU/EOS:  6 weeks
DLRM
Cohort 2a expansion: 
µg QW (N = 3):  52 weeksc
SFU/EOS:  6 weeks
Cohort 3:  
µg Q2W (N = 3):  52 weeksc
SFU/EOS:  6 weeks
Cohort 3:  
µg Q2W (N = 3):  52 weeksc
SFU/EOS:  6 weeks
Cohort 4:  
µg QW (N = 6):  52 weeksc
SFU/EOS:  6 weeks
DLRM (if applicable)
DLRM
DLRM
Cohort 5:  
µg Q2W (N = 6):  52 weeksc
SFU/EOS:  6 weeks
DLRM
 
DLRM = dose level review meeting; EOET = end of extended treatment; EOS = end of study; PD = pharmacodynamics; PK = pharmacokinetics; SFU = safety follow-
up; TPI = toxicity probability interval; Q2W = every 2 weeks; QW = every week;  
a Doses for subsequent cohorts will be determined by results of Bayesian TPI and PK/PD modeling of previous cohorts. 
b A DLRM is required for escalation to higher doses but not for allocation of additional subjects to doses equivalent to or lower than previously given that have been 
deemed tolerable. 


Product:  Efavaleukin Alfa 
Protocol Number:  20160283 
Date: 22 June 2021 
Page 18 of 148 
 
CONFIDENTIAL 
Version 15.1, 14 Apr 2017 
 
c At the discretion of the Sponsor, following discussion and agreement between the principal investigator and medical monitor, subjects responding to efavaleukin alfa 
(as assessed by the end of week 50), who wish to continue treatment, will complete week 52 assessments and may continue to receive efavaleukin alfa treatment at 
their current dosing regimen for up to an additional 52 weeks.  The remaining subjects will complete the week 52/EOT visit.  All subjects who continue to receive 
efavaleukin alfa during the extended dosing period will be reevaluated at week 76 for their response to treatment.  Following discussion and agreement between the 
principal investigator and medical monitor, the Sponsor may decide to allow these subjects to continue treatment through week 102 (Q2W dose) or week 103 (QW 
dose).  Subjects participating in extended dosing through week 104 will complete the week 104/EOET visit (see Table 2-3).  At the discretion of the Sponsor, 
following discussion and agreement between the principal investigator and medical monitor, subjects responding to efavaleukin alfa (as assessed by the 
end of week 104), who wish to continue treatment beyond week 104, may continue to receive efavaleukin alfa treatment at their current dosing regimen 
for up to an additional 156 weeks.  Only subjects who are deemed eligible to continue extended dosing beyond week 102 or week 103 will complete 
dosing at week 104.  The remaining subjects will complete the week 104/EOET visit.  All subjects who continue to receive efavaleukin alfa during the 
extended dosing period will be reevaluated every 6 months for their response to treatment.  Following discussion and agreement between the principal 
investigator and medical monitor, the Sponsor may decide to allow these subjects to continue treatment through week 258 (Q2W dose) or week 259 (QW 
dose).  Subjects participating in extended dosing through week 258 or 259 will complete the week 260/EOET visit (see Table 2-6).  All subjects will complete 
the 6-week safety follow-up after the last dose of efavaleukin alfa. 
Note: All subjects will continue treatment with efavaleukin alfa at their current dose until the 
 
 Subjects who discontinue treatment early (prior to week 50 
[Q2W dosing] or week 51 [QW dosing]) for any reason will complete an end of treatment visit.  Subjects in the extended dosing period who discontinue treatment prior 
to week 258 (Q2W dosing) or week 259 (QW dosing) for any reason will complete an EOET visit within a window of ± 7 days of the next regularly scheduled visit 
after the last dose of efavaleukin alfa, consisting of all assessments included in the week 260 visit.  All subjects will complete a safety follow-up visit 6 weeks 
(± 3 days) after the last dose of efavaleukin alfa. 


Product:  Efavaleukin Alfa 
Protocol Number:  20160283 
Date: 22 June 2021 
Page 19 of 148 
CONFIDENTIAL 
Version 15.1, 14 Apr 2017 
 


Product:  Efavaleukin Alfa 
Protocol Number:  20160283 
Date: 22 June 2021 
Page 20 of 148 
 
CONFIDENTIAL 
Version 15.1, 14 Apr 2017 
 
2.2 
Schedule of Activities 
Table 2-1.  Phase 1b Schedule of Activities – Screening Through Week 5 
 
Screening Baseline 
Treatment Perioda 
Visits for Weekly and Biweekly dosing 
Study Week 
 
 
 
 
2 
3 
4 
5 
PD Visit SFU/EOSb 
Study Day 
-28 
-1 
1 
2 
3 
4 
8 
11 15 22 
29 
30 31 32 36 Anytime 
 
Hours post dose 
 
 
Pre-
dose 
0 0.25 0.5 1 2 6 12 24 48 72 
 
 
 
 
Pre-
dose 
0 6 12 24 48 72 
 
 
 
GENERAL AND SAFETY ASSESSMENTS 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GVHD/Transplant History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital Signs 
X 
X 
X 
 
X 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
ECGc 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Chest X-rayd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/Concomitant 
Medication 
X 
X 
X 
X 
X 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
Corticosteroid usee 
X 
 
X 
X 
X 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
 
 
X 
X 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
Serious Adverse Events 
X 
X 
X 
X 
X 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
Disease-Related Events 
 
 
 
X 
X 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
cGVHD DISEASE ASSESSMENTS 
NIH cGVHD Response 
Assessment (NIH Form A)f 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
GVHD Stagingq 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary Function Testg 
 
Xh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Page 1 of 3 
Footnotes defined on last page of table 


Product:  Efavaleukin Alfa 
Protocol Number:  20160283 
Date: 22 June 2021 
Page 21 of 148 
 
CONFIDENTIAL 
Version 15.1, 14 Apr 2017 
 
Table 2-1.  Phase 1b Schedule of Activities – Screening Through Week 5 
 
Screening Baseline 
Treatment Perioda 
Visits for Weekly and Biweekly dosing 
Study Week 
 
 
 
 
2 
3 
4 
5 
PD Visit 
SFU/EOSb 
Study Day 
-28 
-1 
1 
2 
3 
4 
8 
11 15 22 
29 
30 31 32 36 Anytime 
 
Hours post dose 
 
 
Pre-
dose 
0 0.25 0.5 1 2 6 12 24 48 72 
 
 
 
 
Pre-
dose 0 6 12 24 48 72 
 
 
 
CLINICAL OUTCOME ASSESSMENTS 
LABORATORY ASSESSMENTS 
Clinical Chemistry and 
Hematology 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
X 
 
 
 
 
 
 
X 
X 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testj 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Coagulation (PT, INR, and 
aPTT) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH Test (postmenopausal 
only)k 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, Hepatitis B & C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug and Alcohol Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tuberculosis Testingl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lymphocyte Subsetsm 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
X 
X 
 
 
Biomarker Development 
Samplem 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Pharmacogenetic samplem,n 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PBMCm 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
PHARMACOKINETIC AND ANTIBODY ASSESSMENTS 
 
 
 
 
Page 2 of 3 
Footnotes defined on last page of table 
 


Product:  Efavaleukin Alfa 
Protocol Number:  20160283 
Date: 22 June 2021 
Page 22 of 148 
 
CONFIDENTIAL 
Version 15.1, 14 Apr 2017 
 
Table 2-1.  Phase 1b Schedule of Activities – Screening Through Week 5 
 
Screening Baseline 
Treatment Perioda 
Visits for Weekly and Biweekly dosing 
Study Week 
 
 
 
 
2 
3 
4 
5 
PD Visit 
SFU/EOSb 
Study Day 
-28 
-1 
1 
2 
3 
4 
8 
11 15 22 
29 
30 31 32 36 Anytime 
 
Hours post dose 
 
 
Pre-
dose 
0 0.25 0.5 1 2 6 12 24 48 72 
 
 
 
 
Pre-
dose 0 6 12 24 48 72 
 
 
 
DOSINGp 
Weekly Efavaleukin Alfa 
Administration 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
 
 
 
 
 
X 
 
 
Biweekly Efavaleukin Alfa 
Administration 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
Page 3 of 3 
aPTT = activated partial thromboplastin time; cGVHD = chronic graft versus host disease; CRF = case report form; ECG = electrocardiogram; EOS = end of study for 
individual subject; EOT =  end of treatment; FSH = follicle stimulating hormone; GVHD = graft versus host disease; HIV = human immunodeficiency virus; 
INR = international normalized ratio; IP = investigational product; NIH = National Institutes of Health; PBMC = peripheral blood mononuclear cell; PD = progressive 
disease; PFT = pulmonary function test; PK = pharmacokinetics; PPD = positive purified derivative; PT = prothrombin time; 
 
 SFU = safety follow-up 
a Subjects who withdraw early from treatment will complete the EOT visit and Safety follow-up visit within a window of ± 7 days of the next regularly scheduled 
visit after the last dose of efavaleukin alfa, consisting of all assessments included in the week 52 visit. 
b Safety follow-up visit will be done 6 weeks (± 3 days) after the last dose of efavaleukin alfa.  Women of childbearing potential will be required to complete a pregnancy 
test at this visit. 
c A single ECG will be collected prior to blood draws or other invasive procedures.  See Section 9.2.3.3. 
d Only for subjects with a positive tuberculosis test (ie, positive PPD, indeterminate Quantiferon, or T-SPOT test). 
e Record steroid use and/or changes to dose on concomitant medication CRF page. 
f A 2 or 6 minute walk test is optional for the NIH Form A assessment. 
g PFTs (spirometry) will be used in the NIH Form A assessment unless the subject is unable to comply.  PFTs must be obtained at the Baseline visit unless they were 
performed at the Screening visit.  Thereafter PFTs are strongly preferred at all visits which include the NIH Form A assessment and must be performed for all 
subjects who have an abnormal PFT at Baseline, who have known pulmonary GVHD or who have new pulmonary symptoms.  If PFTs cannot be performed as part 
of the NIH Form A assessment, the lung symptom score should be substituted. 
h PFTs performed at the Screening visit or between the Screening and Baseline visits may be substituted for the Baseline PFT.  However, if historical PFTs are used at 
Screening then PFTs must be performed at the Baseline visit.  Historical PFTs must have been performed within 2 years of the Screening visit. 
j For women of childbearing potential, serum pregnancy test is required at screening.  All other pregnancy tests are urine. 
k Can be done as a part of the clinical chemistry 
l Either a PPD, Quantiferon, or T-SPOT test will be done during screening. 
m Blood samples must be collected prior to administration of investigational product, where appropriate.  Acceptable windows for the timing of blood sample collection 
are as follows:  within 12 hours prior to dose administration for samples collected on days when the investigational product is administered and within ± 12 hours of 
scheduled timepoint for samples collected on days when the investigational product is not administered. 


Product:  Efavaleukin Alfa 
Protocol Number:  20160283 
Date: 22 June 2021 
Page 23 of 148 
 
CONFIDENTIAL 
Version 15.1, 14 Apr 2017 
 
n In subjects who consent to the optional pharmacogenetics testing. 


Product:  Efavaleukin Alfa 
Protocol Number:  20160283 
Date: 22 June 2021 
Page 24 of 148 
 
CONFIDENTIAL 
Version 15.1, 14 Apr 2017 
 
Table 2-2.  Phase 1b Schedule of Activities – Week 6 Through Week 52 
TREATMENT PERIODa 
 
Visits for weekly 
dosing 
Visits for weekly and biweekly dosing 
PD 
Visit 
SFU/ 
EOSb 
Study Week 
19,21,23,25, 
27,29,31,33, 
35,37,39,41, 
43,45,47,49,51 
6 
7 
8 
9 10 11 12 13 14 15 16 17 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 
52/ 
EOTc 
Any-
time 
 
Study Day 
134,148,162, 
176,190,204, 
218,232,246, 
260,274,288, 
302,316,330, 344,358 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
120 
127 
141 
155 
169 
183 
197 
211 
225 
239 
253 
267 
281 
295 
309 
323 
337 
351 
365 
 
 
GENERAL ASSESSMENTS 
Physical Examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
ECGd 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Corticosteroid usee 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serious Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Disease-Related Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Page 1 of 3 
Footnotes defined on last page of table 


Product:  Efavaleukin Alfa 
Protocol Number:  20160283 
Date: 22 June 2021 
Page 25 of 148 
 
CONFIDENTIAL 
Version 15.1, 14 Apr 2017 
 
Table 2-2.  Phase 1b Schedule of Activities – Week 6 Through Week 52 
TREATMENT PERIODa 
 
Visits for weekly 
dosing 
Visits for weekly and biweekly dosing 
PD 
Visit 
SFU/ 
EOSb 
Study Week 
19,21,23,25, 
27,29,31,33, 
35,37,39,41, 
43,45,47,49,51 
6 
7 
8 
9 10 11 12 13 14 15 16 17 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 
52/ 
EOTc 
Any-
time 
 
Study Day 
134,148,162, 
176,190,204, 
218,232,246, 
260,274,288, 
302,316,330, 344,358 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
120 
127 
141 
155 
169 
183 
197 
211 
225 
239 
253 
267 
281 
295 
309 
323 
337 
351 
365 
 
 
cGVHD DISEASE ASSESSMENTS 
NIH cGVHD Response 
Assessment (NIH Form 
A)f 
 
 
 
X 
 
 
 
 
 
 
 
Xg,
n 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
Pulmonary Function 
Testh 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
CLINICAL OUTCOME ASSESSMENTS 
LABORATORY ASSESSMENTS 
Clinical Chemistry and 
Hematology 
 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Pregnancy Testj 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
PHARMACOKINETIC AND ANTIBODY ASSESSMENTS 
 
 
 
 
Page 2 of 3 
Footnotes defined on last page of table 


Product:  Efavaleukin Alfa 
Protocol Number:  20160283 
Date: 22 June 2021 
Page 26 of 148 
 
CONFIDENTIAL 
Version 15.1, 14 Apr 2017 
 
Table 2-2.  Phase 1b Schedule of Activities – Week 6 Through Week 52 
TREATMENT PERIODa 
 
Visits for weekly 
dosing 
Visits for weekly and biweekly dosing 
PD 
Visit 
SFU/ 
EOSb 
Study Week 
19,21,23,25, 
27,29,31,33, 
35,37,39,41, 
43,45,47,49,51 
6 
7 
8 
9 10 11 12 13 14 15 16 17 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 
52/ 
EOTc 
Any-
time 
 
Study Day 
134,148,162, 
176,190,204, 
218,232,246, 
260,274,288, 
302,316,330, 344,358 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
120 
127 
141 
155 
169 
183 
197 
211 
225 
239 
253 
267 
281 
295 
309 
323 
337 
351 
365 
 
 
OTHER 
Lymphocyte Subsetsl 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Biomarker Development 
Samplel 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
PBMCl 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DOSINGm 
Weekly Efavaleukin Alfa 
Administration 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xn 
 
 
Biweekly Efavaleukin 
Alfa Administrationg 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xn 
 
 
Page 3 of 3 
CRF = case report form; cGVHD = chronic graft versus host disease; ECG = electrocardiogram; EOS = end of study for individual subject; EOT = end of therapy; 
GVHD = graft versus host disease; NIH = National Institutes of Health; PBMC = peripheral blood mononuclear cell; PD = progressive disease; PFT = pulmonary 
function test; PK = pharmacokinetics; Q2W = every 2 weeks; 
 SFU = safety follow-up 
a Subjects who withdraw early from treatment will complete the EOT visit and Safety follow-up visit within a window of ± 7 days of the next regularly scheduled 
visit after the last dose of efavaleukin alfa, consisting of all assessments included in the week 52 visit. 
b Safety follow-up visit will be done 6 weeks (± 3 days) after the last dose of efavaleukin alfa.  Women of childbearing potential will be required to complete a pregnancy 
test at this visit. 
c At the discretion of the Sponsor, following discussion and agreement between the principal investigator and medical monitor, subjects responding to efavaleukin alfa 
(as assessed by the end of week 50), who wish to continue treatment, will complete week 52 assessments and may continue to receive efavaleukin alfa treatment at 
their current dosing regimen for up to an additional 52 weeks (see Table 2-3).  The remaining subjects will complete the week 52/EOT visit and 6-weeks of safety 
follow-up after the last dose of efavaleukin alfa. 
d A single ECG will be collected prior to blood draws or other invasive procedures.  See Section 9.2.3.3. 
e Record steroid use and/or changes to dose on concomitant medication CRF page. 
f A 2 or 6 minute walk test is optional for the NIH Form A assessment. 
g For subjects on biweekly dosing arm, beginning at week 18, subjects come in for biweekly visits. 


Product:  Efavaleukin Alfa 
Protocol Number:  20160283 
Date: 22 June 2021 
Page 27 of 148 
 
CONFIDENTIAL 
Version 15.1, 14 Apr 2017 
 
h PFTs (spirometry) will be used in the NIH Form A assessment unless the subject is unable to comply.  PFTs must be obtained at the Baseline visit unless they were 
performed at the Screening visit.  Thereafter PFTs are strongly preferred at all visits which include the NIH Form A assessment and must be performed for all 
subjects who have an abnormal PFT at Baseline, who have known pulmonary GVHD or who have new pulmonary symptoms.  If PFTs cannot be performed as part 
of the NIH Form A assessment, the lung symptom score should be substituted. 
For women of childbearing potential, on study pregnancy tests are urine. 
Doses of investigational product must be given within ± 1 day of the scheduled time point.  Subjects will remain at the site for at least 1 hour following the first and 
second dose of efavaleukin alfa and for 30 minutes following all remaining doses.  Once 
 has been selected, investigational product will be administered within 
 2 days. 
n Subjects continuing to receive treatment during the extended dosing period will receive efavaleukin alfa treatment at the week 52 visit per their current dosing 
regimen. 


Product:  Efavaleukin Alfa 
Protocol Number:  20160283 
Date: 22 June 2021 
Page 28 of 148 
 
CONFIDENTIAL 
Version 15.1, 14 Apr 2017 
 
Table 2-3.  Phase 1b Schedule of Activities – Extended Dosing Period Subjects Only (Week 53 Through Week 104) 
Treatment Perioda 
 
Visits for weekly 
dosing 
Visits for weekly and biweekly dosing 
PD 
Visit 
SFU/ 
EOSb 
Study Week 
53,55,57,59,61, 
63,65,67,69,71, 
73,75,77,79,81, 
83,85,87,89,91, 
93,95,97,99,101, 
103 
54 56 58 60 62 64 66 68 70 72 74 76c 78 80 82 84 86 88 90 92 94 96 98 100 102 
104/ 
EOETd 
Any-
time 
 
Study Day 
372,386,400,414, 
428,442,456,470, 
484,498,512,526, 
540,554,568,582, 
596,610,624,638, 
652,666,680,694, 
708,722 
379 
393 
407 
421 
435 
449 
463 
477 
491 
505 
519 
533 
547 
561 
575 
589 
603 
617 
631 
645 
659 
673 
687 
701 
715 
729 
 
 
GENERAL ASSESSMENTS 
Physical Examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
ECGe 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X  
X 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Corticosteroid usef 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serious Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Disease-Related Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
NIH cGVHD Response 
Assessment (NIH Form 
A)g 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Pulmonary Function 
Testh 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Page 1 of 2 
Footnotes defined on last page 


Product:  Efavaleukin Alfa 
Protocol Number:  20160283 
Date: 22 June 2021 
Page 29 of 148 
 
CONFIDENTIAL 
Version 15.1, 14 Apr 2017 
 
Table 2-3.  Phase 1b Schedule of Activities – Extended Dosing Period Subjects Only (Week 53 Through Week 104) 
Treatment Perioda 
 
Visits for weekly 
dosing 
Visits for weekly and biweekly dosing 
PD 
Visit 
SFU/ 
EOSb 
Study Week 
53,55,57,59,61, 
63,65,67,69,71, 
73,75,77,79,81, 
83,85,87,89,91, 
93,95,97,99,101, 
103 
54 56 58 60 62 64 66 68 70 72 74 76c 78 80 82 84 86 88 90 92 94 96 98 100 102 
104/ 
EOETd 
Any-
time 
 
Study Day 
372,386,400,414, 
428,442,456,470, 
484,498,512,526, 
540,554,568,582, 
596,610,624,638, 
652,666,680,694, 
708,722 
379 
393 
407 
421 
435 
449 
463 
477 
491 
505 
519 
533 
547 
561 
575 
589 
603 
617 
631 
645 
659 
673 
687 
701 
715 
729 
 
 
CLINICAL OUTCOME ASSESSMENTS 
LABORATORY ASSESSMENTS 
Clinical Chemistry and 
Hematology 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Pregnancy Testj 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
PHARMACOKINETIC AND ANTIBODY ASSESSMENTS 
 
 
 
 
OTHER 
Lymphocyte Subsetsl 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
Biomarker 
Development Samplel 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
DOSE 
Weekly Efavaleukin 
Alfa Administrationm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xn 
 
 
Biweekly Efavaleukin 
Alfa Administrationm 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xn 
 
 
Page 2 of 2 


Product:  Efavaleukin Alfa 
Protocol Number:  20160283 
Date: 22 June 2021 
Page 30 of 148 
 
CONFIDENTIAL 
Version 15.1, 14 Apr 2017 
 
CRF = case report form; cGVHD = chronic graft versus host disease; ECG = electrocardiogram; EOS = end of study for individual subject; EOET = end of extended 
treatment; GVHD = graft versus host disease; NIH = National Institutes of Health; PD = progressive disease; PFT = pulmonary function test; PK = pharmacokinetics; 
Q2W = twice weekly; QW = every week; 
; SFU = safety follow-up 
a Subjects who withdraw early from treatment will complete the EOET visit and Safety follow-up visit within a window of ± 7 days of the next regularly 
scheduled visit after the last dose of efavaleukin alfa, consisting of all assessments included in the week 104 visit. 
b Safety follow-up visit will be done 6 weeks (± 3 days) after the last dose of efavaleukin alfa.  Women of childbearing potential will be required to complete a pregnancy 
test at this visit. 
c Re-assessment of subject’s response to efavaleukin alfa treatment will be conducted at week 76 and a decision may be made by the Sponsor, following discussion 
and agreement between the principal investigator and medical monitor, to allow subjects who wish to, to continue treatment through week 102 (Q2W dose) or week 
103 (QW dose). 
d Subjects in the extended dosing period who discontinue treatment prior to week 258 (Q2W dosing) or week 259 (QW dosing) for any reason will complete an EOET 
visit and 6-weeks of safety follow-up after the last dose of efavaleukin alfa. 
e A single ECG will be collected prior to blood draws or other invasive procedures.  See Section 9.2.3.3.  
f Record steroid use and/or changes to dose on concomitant medication CRF page. 
g A 2 or 6 minute walk test is optional for the NIH Form A assessment. 
h PFTs (spirometry) will be used in the NIH Form A assessment unless the subject is unable to comply.  PFTs must be obtained at the Baseline visit unless they were 
performed at the Screening visit.  Thereafter PFTs are strongly preferred at all visits which include the NIH Form A assessment and must be performed for all 
subjects who have an abnormal PFT at Baseline, who have known pulmonary GVHD or who have new pulmonary symptoms.  If PFTs cannot be performed as part 
of the NIH Form A assessment, the lung symptom score should be substituted. 
Doses of investigational product must be given within ± 1 day of the scheduled time point.  Subjects will remain at the site for at least 30 minutes following doses of 
investigational product.  Once 
 has been selected, investigational product will be administered within  2 days. 
n At the discretion of the Sponsor, following discussion and agreement between the principal investigator and medical monitor, subjects responding to 
efavaleukin alfa (as assessed by the end of week 104), who wish to continue treatment beyond week 104, may continue to receive efavaleukin alfa 
treatment at their current dosing regimen for up to an additional 156 weeks.  Only subjects who are deemed eligible to continue extended dosing beyond 
week 102 or week 103 will complete dosing at week 104.  The remaining subjects will complete the week 104/EOET visit.   
 
 


Product:  Efavaleukin Alfa 
Protocol Number:  20160283 
Date: 22 June 2021 
Page 31 of 148 
 
CONFIDENTIAL 
Version 15.1, 14 Apr 2017 
 
Table 2-4.  Phase 1b Schedule of Activities – Extended Dosing Period Subjects Only (Week 105 Through Week 158) 
TREATMENT PERIODa 
 
Visits for weekly 
dosing 
Visits for weekly and biweekly dosing 
PD 
Visit 
SFU/ 
EOSb 
Study Week 
105,107,109,111, 
113,115,117,119, 
121,123,125,127, 
129,131,133,135, 
137, 139, 141, 143, 
145,147,149,151, 
153,155,157 
106 108 110 112 114 116 118 120 122 124 126 128 130c 132 134 136 138 140 142 144 146 148 150 152 154 156 158 Any-
time 
 
GENERAL ASSESSMENTS 
Physical Examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
ECGd 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Corticosteroid usee 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serious Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
NIH cGVHD Response 
Assessment (NIH Form 
A)f 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Pulmonary Function 
Testg 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
CLINICAL OUTCOME ASSESSMENTS 
LABORATORY ASSESSMENTS 
Clinical Chemistry and 
Hematology 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
X 
Pregnancy Testi 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
X 
Page 1 of 2 
Footnotes are defined on the last page of the table. 


Product:  Efavaleukin Alfa 
Protocol Number:  20160283 
Date: 22 June 2021 
Page 32 of 148 
 
CONFIDENTIAL 
Version 15.1, 14 Apr 2017 
 
Table 2-4.  Phase 1b Schedule of Activities – Extended Dosing Period Subjects Only (Week 105 Through Week 158) 
TREATMENT PERIODa 
 
Visits for weekly 
dosing 
Visits for weekly and biweekly dosing 
PD 
Visit 
SFU/ 
EOSb 
Study Week 
105,107,109,111, 
113,115,117,119, 
121,123,125,127, 
129,131,133,135, 
137, 139, 141, 143, 
145,147,149,151, 
153,155,157 
106 108 110 112 114 116 118 120 122 124 126 128 130c 132 134 136 138 140 142 144 146 148 150 152 154 156 158 Any-
time 
 
PHARMACOKINETIC AND ANTIBODY ASSESSMENTS 
 
 
OTHER 
Lymphocyte Subsetsk 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Biomarker Development 
Samplek 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
DOSE 
Weekly Efavaleukin Alfa 
Administrationl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Biweekly Efavaleukin 
Alfa Administrationl 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Page 2 of 2 
CRF = case report form; cGVHD = chronic graft versus host disease; ECG = electrocardiogram; EOS = end of study for individual subject; EOET = end of 
extended treatment; GVHD = graft versus host disease; NIH = National Institutes of Health; PD = progressive disease; PFT = pulmonary function test; 
PK = pharmacokinetics; Q2W = every 2 weeks; QW = every week; 
; 
 
SFU = safety follow-up 
Subjects in the extended dosing period who discontinue treatment prior to week 258 (Q2W dosing) or week 259 (QW dosing) for any reason will complete 
an EOET visit and 6-weeks of safety follow-up after the last dose of efavaleukin alfa.  See Table 2-6. 
a Subjects who withdraw early from treatment will complete the EOET visit and Safety follow-up visit within a window of ± 7 days of the next regularly 
scheduled visit after the last dose of efavaleukin alfa, consisting of all assessments included in the week 260 visit. 
b Safety follow-up visit will be done 6 weeks (± 3 days) after the last dose of efavaleukin alfa.  Women of childbearing potential will be required to complete 
a pregnancy test at this visit. 
c Re-assessment of subject’s response to efavaleukin alfa treatment will be conducted every 6 months and a decision may be made by the Sponsor, 
following discussion and agreement between the principal investigator and medical monitor, to allow subjects who wish to, to continue treatment 
through week 258 (Q2W dose) or week 259 (QW dose). 
d A single ECG will be collected prior to blood draws or other invasive procedures.  See Section 9.2.3.3.  


Product:  Efavaleukin Alfa 
Protocol Number:  20160283 
Date: 22 June 2021 
Page 33 of 148 
 
CONFIDENTIAL 
Version 15.1, 14 Apr 2017 
 
e Record steroid use and/or changes to dose on concomitant medication CRF page. 
f A 2 or 6 minute walk test is optional for the NIH Form A assessment. 
g PFTs (spirometry) will be used in the NIH Form A assessment unless the subject is unable to comply.  PFTs must be obtained at the Baseline visit unless 
they were performed at the Screening visit.  Thereafter PFTs are strongly preferred at all visits which include the NIH Form A assessment and must be 
performed for all subjects who have an abnormal PFT at Baseline, who have known pulmonary GVHD or who have new pulmonary symptoms.  If PFTs 
cannot be performed as part of the NIH Form A assessment, the lung symptom score should be substituted. 
For women of childbearing potential, on study pregnancy tests are urine. 
l Doses of investigational product in phase 1b must be given within ± 3 days from the scheduled visit for subjects in Q2W dosing and ± 2 days from the 
scheduled visit for QW dosing.  Subjects will remain at the site for at least 30 minutes following doses of investigational product.  Once 
 has been 
selected, investigational product will be administered within  2 days. 
 
 


Product:  Efavaleukin Alfa 
Protocol Number:  20160283 
Date: 22 June 2021 
Page 34 of 148 
 
CONFIDENTIAL 
Version 15.1, 14 Apr 2017 
 
Table 2-5.  Phase 1b Schedule of Activities – Extended Dosing Period Subjects Only (Week 159 Through Week 222) 
TREATMENT PERIODa 
 
Visits for weekly 
dosing 
Visits for weekly and biweekly dosing 
PD 
Visit 
SFU/ 
EOSb 
Study Week 
159,161,163,165, 
167,169,171,173, 
175,177,179,181, 
183,185,187,189, 
191,193,195,197, 
197,199,201,203, 
205,207,209,221 
160 162 164 166 168 170 172 174 176 178 180 182c 184 186 188 190 192 194 196 198 200 202 204 206 208c 210 222 Any-
time 
 
GENERAL ASSESSMENTS 
Physical Examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
ECGd 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Corticosteroid usee 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serious Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
NIH cGVHD Response 
Assessment (NIH Form 
A)f 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
Pulmonary Function 
Testg 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
CLINICAL OUTCOME ASSESSMENTS 
LABORATORY ASSESSMENTS 
Clinical Chemistry and 
Hematology 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
Pregnancy Testi 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
Page 1 of 2 
Footnotes are defined on the last page of the table. 


Product:  Efavaleukin Alfa 
Protocol Number:  20160283 
Date: 22 June 2021 
Page 35 of 148 
 
CONFIDENTIAL 
Version 15.1, 14 Apr 2017 
 
Table 2-5.  Phase 1b Schedule of Activities – Extended Dosing Period Subjects Only (Week 159 Through Week 222) 
TREATMENT PERIODa 
 
Visits for weekly 
dosing 
Visits for weekly and biweekly dosing 
PD 
Visit 
SFU/ 
EOSa 
Study Week 
159,161,163,165, 
167,169,171,173, 
175,177,179,181, 
183,185,187,189, 
191,193,195,197, 
197,199,201,203, 
205,207,209,221 
160 162 164 166 168 170 172 174 176 178 180 182 184 186 188 190 192 194 196 198 200 202 204 206 208 210 222 Any-
time 
 
PHARMACOKINETIC AND ANTIBODY ASSESSMENTS 
 
 
OTHER 
Lymphocyte Subsetsk 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Biomarker Development 
Samplek 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
DOSE 
Weekly Efavaleukin Alfa 
Administrationl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Biweekly Efavaleukin 
Alfa Administrationl 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Page 2 of 2 
CRF = case report form; cGVHD = chronic graft versus host disease; ECG = electrocardiogram; EOS = end of study for individual subject; EOET = end of 
extended treatment; GVHD = graft versus host disease; NIH = National Institutes of Health; PD = progressive disease; PFT = pulmonary function test; 
PK = pharmacokinetics; Q2W = every 2 weeks; QW = every week; 
 
 
SFU = safety follow-up 
Subjects in the extended dosing period who discontinue treatment prior to week 258 (Q2W dosing) or week 259 (QW dosing) for any reason will complete 
an EOET and 6-weeks of safety follow-up after the last dose of efavaleukin alfa.  See Table 2-6. 
a Subjects who withdraw early from treatment will complete the EOET visit and Safety follow-up visit. within a window of ± 7 days of the next regularly 
scheduled visit after the last dose of efavaleukin alfa, consisting of all assessments included in the week 260 visit 
b Safety follow-up visit will be done 6 weeks (± 3 days) after the last dose of efavaleukin alfa.  Women of childbearing potential will be required to complete 
a pregnancy test at this visit. 
c Re-assessment of subject’s response to efavaleukin alfa treatment will be conducted every 6 months and a decision may be made by the Sponsor, 
following discussion and agreement between the principal investigator and medical monitor, to allow subjects who wish to, to continue treatment 
through week 258 (Q2W dose) or week 259 (QW dose). 
d A single ECG will be collected prior to blood draws or other invasive procedures.  See Section 9.2.3.3.  


Product:  Efavaleukin Alfa 
Protocol Number:  20160283 
Date: 22 June 2021 
Page 36 of 148 
 
CONFIDENTIAL 
Version 15.1, 14 Apr 2017 
 
e Record steroid use and/or changes to dose on concomitant medication CRF page. 
f A 2 or 6 minute walk test is optional for the NIH Form A assessment. 
g PFTs (spirometry) will be used in the NIH Form A assessment unless the subject is unable to comply.  PFTs must be obtained at the Baseline visit unless 
they were performed at the Screening visit.  Thereafter PFTs are strongly preferred at all visits which include the NIH Form A assessment and must be 
performed for all subjects who have an abnormal PFT at Baseline, who have known pulmonary GVHD or who have new pulmonary symptoms.  If PFTs 
For women of childbearing potential, on study pregnancy tests are urine. 
e 
scheduled visit for QW dosing.  Subjects will remain at the site for at least 30 minutes following doses of investigational product.  Once 
 has been 
selected, investigational product will be administered within  2 days. 
 
 


Product:  Efavaleukin Alfa 
Protocol Number:  20160283 
Date: 22 June 2021 
Page 37 of 148 
 
CONFIDENTIAL 
Version 15.1, 14 Apr 2017 
 
Table 2-6.  Phase 1b Schedule of Activities – Extended Dosing Period Subjects Only (Week 223 Through Week 260) 
TREATMENT PERIODa 
 
Visits for weekly 
dosing 
Visits for weekly and biweekly dosing 
PD 
Visit 
SFU/ 
EOSb 
Study Week 
223,225,227,229, 
231,233,235,237, 
239,241,243,245, 
247,249,251,253, 
257,259 
224 
226 
228 
230 
232 234c 
236 
240 
242 
244 
246 
248 
250 
252 
254 
256 
258 
260/ 
EOETd Any-
time 
 
GENERAL ASSESSMENTS 
Physical Examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
ECGe 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Corticosteroid usef 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serious Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Disease-Related Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
NIH cGVHD Response 
Assessment (NIH Form A)g 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Pulmonary Function Testh 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
CLINICAL OUTCOME ASSESSMENTS 
LABORATORY ASSESSMENTS 
Clinical Chemistry and 
Hematology 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
Pregnancy Testj 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
Page 1 of 2 
Footnotes are defined on the last page of the table. 


Product:  Efavaleukin Alfa 
Protocol Number:  20160283 
Date: 22 June 2021 
Page 38 of 148 
 
CONFIDENTIAL 
Version 15.1, 14 Apr 2017 
 
Table 2-6.  Phase 1b Schedule of Activities – Extended Dosing Period Subjects Only (Week 223 Through Week 260) 
TREATMENT PERIODa 
 
Visits for weekly 
dosing 
Visits for weekly and biweekly dosing 
PD 
Visit 
SFU/ 
EOSa 
Study Week 
223,225,227,229, 
231,233,235,237, 
239,241,243,245, 
247,249,251,253, 
257,259 
224 
226 
228 
230 
232 
234 
236 
240 
242 
244 
246 
248 
250 
252 
254 
256 
258 
260/ 
EOET 
Any-
time 
 
PHARMACOKINETIC AND ANTIBODY ASSESSMENTS 
 
 
OTHER 
Lymphocyte Subsetsl 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Biomarker Development 
Samplel 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
DOSE 
Weekly Efavaleukin Alfa 
Administrationm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Biweekly Efavaleukin Alfa 
Administrationm 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Page 2 of 2 
CRF = case report form; cGVHD = chronic graft versus host disease; ECG = electrocardiogram; EOS = end of study for individual subject; EOET = end of 
extended treatment; GVHD = graft versus host disease; NIH = National Institutes of Health; PD = progressive disease; PFT = pulmonary function test; 
PK = pharmacokinetics; Q2W = every 2 weeks; QW = every week;
; SFU = safety follow-up 
a Subjects who withdraw early from treatment will complete the EOET visit and Safety follow-up visit within a window of ± 7 days of the next regularly 
scheduled visit after the last dose of efavaleukin alfa, consisting of all assessments included in the week 260 visit. 
b Safety follow-up visit will be done 6 weeks (± 3 days) after the last dose of efavaleukin alfa.  Women of childbearing potential will be required to complete 
a pregnancy test at this visit. 
c Re-assessment of subject’s response to efavaleukin alfa treatment will be conducted every 6 months and a decision may be made by the Sponsor, 
following discussion and agreement between the principal investigator and medical monitor, to allow subjects who wish to, to continue treatment 
through week 258 (Q2W dose) or week 259 (QW dose). 
d Subjects in the extended dosing period who discontinue treatment prior to week 258 (Q2W dosing) or week 259 (QW dosing) for any reason will complete 
an EOET visit and 6-weeks of safety follow-up after the last dose of efavaleukin alfa. 
e A single ECG will be collected prior to blood draws or other invasive procedures.  See Section 9.2.3.3.  
f Record steroid use and/or changes to dose on concomitant medication CRF page. 
g A 2 or 6 minute walk test is optional for the NIH Form A assessment. 


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h PFTs (spirometry) will be used in the NIH Form A assessment unless the subject is unable to comply.  PFTs must be obtained at the Baseline visit unless 
they were performed at the Screening visit.  Thereafter PFTs are strongly preferred at all visits which include the NIH Form A assessment and must be 
performed for all subjects who have an abnormal PFT at Baseline, who have known pulmonary GVHD or who have new pulmonary symptoms.  If PFTs 
cannot be performed as part of the NIH Form A assessment, the lung symptom score should be substituted. 
j For women of childbearing potential, on study pregnancy tests are urine. 
m Doses of investigational product in phase 1b must be given within ± 3 days from the scheduled visit for subjects in Q2W dosing and ± 2 days from the 
scheduled visit for QW dosing.  Subjects will remain at the site for at least 30 minutes following doses of investigational product.  Once 
 has been 
selected, investigational product will be administered within  2 days. 
 


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3. 
Introduction 
3.1 
Study Rationale 
This open-label, multicenter, phase 1b/2 study is planned to evaluate the safety and 
efficacy of efavaleukin alfa (AMG 592) in subjects with steroid refractory chronic graft 
versus host disease (cGVHD).  The phase 1b part of the study will evaluate the safety, 
pharmacokinetics (PK), and pharmacodynamics (PD) of efavaleukin alfa and will define 
the maximum tolerated dose (MTD) and/or a biologically optimal dose.  
 
3.2 
Background 
3.2.1 
Disease 
Chronic graft-versus-host disease (cGVHD) is a systemic inflammatory disorder that is 
associated with considerable morbidity and mortality and develops in more than half of 
long term survivors after hematopoietic stem-cell transplantation (HSCT) (Kahl, 2007).  
It is the most common long-term complication of allogeneic HSCT and the leading cause 
of 
  The median time to onset is 4 to 6 months after HSCT 
but 5% to 10% of cases are diagnosed at greater than 1 year after HSCT 
(Lee and Flowers, 2008).  Per 21 CFR 312.300, cGVHD meets the definition of a serious 
condition as it is a condition associated with morbidity that has a substantial impact on 
day to day function.  Improved treatment for cGVHD is a major unmet need. 
First line therapy for moderate to severe cGVHD consists of systemic glucocorticoid 
therapy or calcineurin inhibitors.  Treatment with systemic glucocorticoids has limited 
efficacy, with half of patients requiring second-line therapy, and is associated with 
substantial long-term toxicity. 
Second-line therapy for those who fail systemic glucocorticoids is not well established.  
Estimated response rates to experimental therapy are confounded by the lack of 
controlled trials and the non-standardized use of outcome measures.  
 
 
 
 
.  However, few multi-center controlled trials have replicated these 
high response rates.  For instance, a recent multi-center randomized controlled phase 2 
cross-over trial comparing imatinib versus rituximab for cutaneous sclerosis associated 


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with cGVHD reported a significant clinical response in 26% of patients in the imatinib 
arm versus 27% of subjects in the rituximab arm.  Furthermore, only 17% of 
imatinib-treated subjects and 14% of rituximab-treated subjects achieved ‘treatment 
success’, defined as a significant clinical response without cross-over, relapse, or death 
(Arai et al, 2016). 
With regard to the expected response rate with current standard of care (SOC), few 
studies include an SOC arm for comparison.  The largest relevant study 
(n = 151 evaluable patients), a double-blind, randomized controlled trial comparing 
mycophenolate mofetil (MMF) plus SOC versus SOC alone, demonstrated that only 
18% in the SOC arm versus 23% in the MMF plus SOC met the primary endpoint of 
complete withdrawal of systemic immunosuppressant therapy after 2 years (p = NS) 
(Martin, 2009).  A study of Extra Corporeal Photophoresis (ECP) versus SOC reported a 
blinded evaluation of the Total Skin Score of 8.5% in the SOC arm versus 14.5% in the 
ECP arm (Flowers, 2008). 
There is currently 1 approved, commercially available drug in the US and Canada for the 
treatment of patients with steroid-refractory cGVHD.  Ibrutinib, an inhibitor of Bruton’s 
tyrosine kinase (BTK), was approved in 2017 for the treatment of adults with cGVHD 
after failure of 1 or more lines of systemic therapy.  
 
 
 
 
The pathogenesis of cGVHD is complex and incompletely understood.  It is 
characterized by aberrant negative selection of autoreactive T cells due to thymic 
dysfunction, autoantibody production, and fibrotic injury (Cutler et al, 2017; 
MacDonald et al, 2017; Soci and Ritz, 2014; Blazar et al, 2012).   
Regulatory T cells (Treg) are a subset of cluster of differentiation (CD)4 T cells that 
suppress inflammation and whose numbers and function are maintained by interleukin-2 
(IL-2).  A loss in the homeostatic balance between Treg and other lymphocytes is 
considered a causative factor in many inflammatory conditions, including cGVHD.  Low 
dose IL-2 and recombinant IL-2 (Proleukin® [aldesleukin]) have been studied in active 
cGVHD subjects (Koreth et al, 2016; Koreth et al, 2011).  Disease improvement has 
generally been associated with sustained Treg expansion in vivo without increases in 
rates of infection or cancer relapse.  However, the narrow window between adequate 
Treg enrichment and side effects (nausea, fever, fatigue) due to stimulation of T effector 


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cells (Teff) and natural killer (NK) cells may limit achievement of optimal Treg expansion 
(Koreth et al, 2011).  Notably, a dose of 3 x 106 IU/m2 induced persistent National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE 
version 4.03) grade 1 constitutional symptoms (fever, malaise, and arthralgia), 
necessitating a 50% dose reduction, and indicating a narrow therapeutic window 
between adequate Treg enrichment and stimulation of effector cells (Koreth et al, 2011). 
3.2.2 
Amgen Investigational Product Background:  Efavaleukin Alfa 
Efavaleukin alfa is an Fc IL-2 mutein fusion protein designed to increase Treg selectivity, 
which has been developed to expand Tregs in subjects with inflammatory diseases 
(refer to the Investigator’s Brochure).  Interleukin-2 is a key growth factor for Tregs and 
is essential for Treg development, homeostasis and function.  At low dose IL-2 binds 
preferentially to the α subunit (CD25) of the high-affinity IL-2 receptor which is expressed 
constitutively by Tregs and is absent on naive Tcells and unactivated T memory cells.  
This results in selective activation of Tregs.  However, at higher doses IL-2 also 
activates other immune cells such as CD4+ and CD8+ T effector cells, NK cells and 
natural killer T cells (NKT) via the dimeric low affinity IL-2 receptor.  Compared with 
aldesleukin, efavaleukin alfa exhibits greatly improved selectivity for Tregs over Teff and 
NK cells both in vitro and in vivo, potentially resulting in an improved therapeutic margin.  
In addition, the Fc domain of efavaleukin alfa provides a prolonged half-life compared 
with aldesleukin, thus reducing dosing frequency to maintain Treg enrichment.  
Treatment in subjects with steroid-refractory cGVHD with efavaleukin alfa is anticipated 
to provide greater sustained Treg expansion and an improved safety profile, leading to 
greater efficacy and tolerability. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of 
efavaleukin alfa is provided in the Investigator’s Brochure. 
3.2.2.1 
Toxicology 
In the 1- and 3-month repeat-dose toxicology studies in the cynomolgus monkey (dose 
levels up to 300 and 100 µg/kg, respectively, weekly subcutaneous [SC] injection), the 
no observed adverse effect level (NOAEL) dose was 30 µg/kg based on the observation 
of increased heart rate with attenuated diurnal rhythm at 100 µg/kg or greater.  In 
addition, reversible decreases in red blood cell (RBC) mass, platelet and neutrophil 
counts were observed at 300 µg/kg in the 1-month study.  In the rat single-dose safety 
pharmacology study evaluating respiratory function (dose levels:  100, 500, and 
2000 µg/kg, single SC injection), audible respiration, decreased tidal volume and 


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increased respiration rate were observed at 2000 µg/kg.  The heart rate, hematologic 
and respiratory changes were reversible, and are considered clinically monitorable. 
3.2.2.2 
Human Exposure 
The observed efavaleukin alfa human exposures from cohorts 1 through 8 (
 to 
 µg) of the single ascending dose (SAD) first in human (FIH) study in healthy 
subjects and all available PK data from 3 phase 1b studies:  20170103 (up to 
 µg 
every 2 weeks [Q2W] in subjects with systemic lupus erythematosus [SLE]); 20170149 
(up to 
 µg Q2W in subject with rheumatoid arthritis [RA]); and this study, 20160283 
(up to 
 µg Q2W) were used to predict efavaleukin alfa exposures in humans 
following 
and 
 µg doses given every week (QW) and 
 and 
 µg 
doses given Q2W.  Accumulation of efavaleukin alfa is not expected, therefore at steady 
state, exposures (area under the concentration-time curve [AUC] and maximum 
observed concentration [Cmax]) are predicted to be within the range of 
 
 attained after a single dose (Table 3-1).  Safety margins (Table 3-1) 
based on the efavaleukin alfa AUC and Cmax observed at the NOAEL of 30 µg/kg from 
the 3-month repeat-dose GLP toxicology study in cynomolgus monkey are predicted to 
be 9.1-fold and 1.3-fold at the administration of 
 µg Q2W, the dose expected to 
result in the highest exposures and support administration of this dose. 


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Table 3-1.  Predicted Efavaleukin Alfa Steady State Exposures After 
16 Weekly Subcutaneous Administrations of Efavaleukin Alfa in cGVHD Subjects 
for the Proposed Doses and Margins Relative to the 3-month GLP Repeat-dose 
Cynomolgus Monkey Exposure at the NOAEL of 30 µg/kg (Study 20160283) 
Clinical Dose (µg) 
Median (IQR) 
Exposure Marginb 
AUCtaua 
(hr•ng/mL) 
Cmaxa (ng/mL) 
AUC 
Cmax 
(Q2W) 
549 
(373-801) 
18.9 
(15.0-23.1) 
35 
4.7 
 (QW) 
274 
(195-395) 
10.3 
(8.1-12.6) 
35 
8.5 
 (Q2W) 
1028 
(719-1488) 
35.4 
(28.3-43.4) 
18 
2.5 
 (QW) 
553 
(399-778) 
20.3 
(16.5-25.0) 
17 
4.3 
 (Q2W) 
2070 
(1401-2938) 
70.3 
(55.6-86.7) 
9.1 
1.3 
AUC = area under the concentration-time curve; AUCtau = area under the concentration-time curve over a 
dosing interval; Cmax = maximum observed concentration; GLP = good laboratory practice; 
IQR = interquartile range; NOAEL = no observed adverse effect level; QW = every week; Q2W = every 2 
weeks 
a Exposure after the first and last doses are predicted to be similar, steady state Cmax and AUCtau (AUC for 
the last dosing interval) are used for margin calculation.  
b Toxicokinetic results (Study 118065) in monkey last week of dosing at 30 µg/kg once weekly, mean 
AUC7,wk13 (area under the concentration-time profile from day 1 to day 7 of week 13) = 9490 hr•ng/mL, 
last dose mean Cmax,wk13 = 88 ng/mL from 4 of 8 animals that sustained efavaleukin alfa exposure 
throughout the 3-month administration period:  Exposure margin for AUC for Q2W dosing was based on 
9490 hr•ng/mL x 2. 
3.2.2.3 
Clinical Experience 
As of 22 September 2020, approximately 136 subjects have received single or multiple 
doses of efavaleukin alfa, including healthy subjects in a phase 1a FIH study 
(20140324), Japanese healthy subjects in a phase 1a study (20180132), subjects with 
RA in a phase 1b study (20170149), and subjects in 2 ongoing clinical studies in 
subjects with SLE (20170103; phase 1b), and steroid-refractory cGHVD (20160283; 
phase 1b/2).  Detailed information about clinical experience with efavaleukin alfa may be 
found in the Investigator’s Brochure. 
3.2.3 
Risk Assessment 
The most common adverse events experienced by subjects included mild (grade 1) 
painless erythema at or near the injection site, sometimes accompanied by pruritus, that 
was self-resolving.  As of 22 September 2020, 2 serious hypersensitivity reactions to 
efavaleukin alfa have been reported.  The 2 events (grade 2 and 3, respectively) 


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occurred within the first 24 hours after initial dose and resolved without sequalae with 
symptomatic treatment (ie, systemic corticosteroids).  More detailed information about 
the safety risks of efavaleukin alfa may be found in the Investigator’s Brochure. 
3.2.4 
Experience With Other Similar Biological Agents 
Low dose recombinant IL-2 has been administered SC to healthy subjects as well as to 
small numbers of patients in clinical trials in multiple indications including cGVHD, 
Type 1 Diabetes, SLE, alopecia areata and HCV vasculitis (He et al, 2016; 
Koreth et al, 2016; Hartemann et al, 2013; Castela et al, 2014; Ito et al, 2014; 
Koreth et al, 2011; Sadoun et al, 2011).  Dosing regimens have ranged between 
0.33 million IU and 3 million IU/m2 daily with varying treatment intervals.  The overall 
safety profile of low dose IL-2 has been acceptable.  The most common reported 
adverse events across trials include flu-like constitutional symptoms (malaise, fatigue, 
arthralgia, and myalgia), typically grade 1 to 3, which resolved upon dose reduction or 
cessation of treatment.  Grade 1 to 3 injection site reactions were also commonly 
reported.  Five grade 3 or higher infections were reported in 63 cGVHD patients 
(Koreth et al, 2016; Koreth et al, 2011) and one grade 2 dental abscess was reported in 
10 patients with HCV vasculitis treated with low dose recombinant IL-2 
(Sadoun et al, 2011).  Increased rates of infection have not been reported.  Treatment 
with low dose IL-2 administered SC has not been associated with capillary leak 
syndrome, cytokine release syndrome, pulmonary edema, cardiac toxicities or other 
severe IL-2 related toxicities.  In summary, efavaleukin alfa is expected to be 
well-tolerated compared to aldesleukin due to its wider therapeutic window and the 
safety profile observed to date in healthy subjects who have received a single dose of 
efavaleukin alfa.  However, subjects will be monitored closely throughout the study. 


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4. 
Objectives, Endpoints and Hypotheses 
4.1 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
Phase 1b 
 
To evaluate the safety and tolerability of 
multiple ascending doses of efavaleukin 
alfa in subjects with steroid refractory 
cGVHD in order to estimate the MTD and 
establish the 
 
Phase 1b 
 
Incidence of dose limiting toxicities (DLTs) 
at first 4 weeks 
 
Incidence of all treatment-related and 
treatment-emergent adverse events and 
serious adverse event 
Secondary 


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Objectives 
Endpoints 
 
 
Exploratory 


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4.2 
Hypotheses 
Phase 1b 
Efavaleukin alfa will be safe and well-tolerated in subjects with steroid refractory cGVHD. 
5. 
Study Design 
5.1 
Overall Design 
This is an open-label, multi-center phase 1b/2 study to evaluate the safety and efficacy 
of efavaleukin alfa in subjects with steroid refractory cGVHD.  The study will be 
conducted in 2 phases: 
5.1.1 
Phase 1b 
The phase 1b part of this study will be conducted as a multiple ascending dose (MAD) 
study.  Each dosing cohort will consist of between 3 and 6 DLT-evaluable subjects who 
will receive efavaleukin alfa SC either QW or Q2W plus protocol permitted background 
therapy for 52 weeks.  The DLT evaluation period is 4 weeks after the first dose of study 
drug.  At the discretion of the Sponsor, following discussion and agreement between the 
principal investigator and medical monitor, subjects responding to efavaleukin alfa (as 
assessed by the end of week 50), who wish to continue treatment, may continue to 
receive efavaleukin alfa treatment at their current dosing regimen for up to an additional 
52 weeks.  The remaining subjects will complete the week 52/EOT visit.  All subjects 
who continue to receive efavaleukin alfa during the extended dosing period will be 
reevaluated at week 76 for their response to treatment.  Following discussion and 
agreement between the principal investigator and medical monitor, the Sponsor may 
decide to allow these subjects to continue treatment through week 102 (Q2W dose) or 
week 103 (QW dose).  Subjects participating in extended dosing through week 104 will 
complete the week 104/end of extended treatment (EOET) visit (see Table 2-3).  At 
the discretion of the Sponsor, following discussion and agreement between the 
principal investigator and medical monitor, subjects responding to efavaleukin 
alfa (as assessed by the end of week 104), who wish to continue treatment beyond 
week 104, may continue to receive efavaleukin alfa treatment at their current 
dosing regimen for up to an additional 156 weeks.  Only subjects who are deemed 
eligible to continue extending dosing beyond week 102 or week 103 will complete 


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dosing at week 104.  The remaining subjects will complete the week 104/EOET 
visit.  All subjects who continue to receive efavaleukin alfa during the extended 
dosing period will be reevaluated every 6 months for their response to treatment.  
Following discussion and agreement between the principal investigator and 
medical monitor, the Sponsor may decide to allow these subjects to continue 
treatment through week 258 (Q2W dose) or week 259 (QW dose).  Subjects 
participating in extended dosing through week 258 or 259 will complete the 
week 260/EOET visit (see Table 2-6).  All subjects will complete the 6-week safety 
follow-up after the last dose of efavaleukin alfa. 
Five dose levels are planned:  
 µg Q2W (cohort 1a), 
 µg QW (cohort 2a), 
 µg 
Q2W (cohort 3), 
 µg QW (cohort 4), and 
 µg Q2W (cohort 5).  Dose levels 1a 
(
 µg Q2W) and 2a (
 µg QW) will be enrolled concurrently.  Three subjects each 
will be assigned to cohorts 1a (
 µg Q2W) and 2a (
 µg QW) alternately (total of 6 
subjects).  After the last subject completes the DLT evaluation period, a dose level 
review meeting (DLRM) will occur and if deemed necessary, 3 additional subjects each 
will be assigned to cohorts 1a and 2a alternately (total of 6 subjects) to gain additional 
information.  After the last subject completes the DLT evaluation period, a DLRM will 
occur and if dose escalation is deemed appropriate, subjects will be enrolled in cohorts 3 
(
 µg Q2W) ,4 (
 µg QW), and 5 (
 µg Q2W) as follows:  first, 3 subjects will 
be enrolled in cohort 3.  An internal safety review will be conducted by the Amgen 
Medical Monitor and Global Safety Officer after the first 3 subjects complete the DLT 
evaluation period.  If concerning safety issues are identified, a DLRM will occur to 
assess if it is safe to proceed with additional enrollment in cohort 3 and concurrent 
enrollment in cohort 4.  If no concerning safety issues are identified in these first 3 
subjects, enrollment of the remaining 3 subjects in cohort 3 will proceed without a 
DLRM.  Concurrently, enrollment of 6 subjects in cohort 4 will begin with alternate 
assignment of subjects between cohorts 3 and 4 until enrollment of cohort 3 has 
completed.  Enrollment of 6 subjects in cohort 5 will begin after the DLRM for cohort 4 is 
complete.  DLRMs for cohorts 3, 4 and 5 will occur after the last subject in that cohort 
completes the DLT evaluation period. 
All planned dose levels for a given cohort may be adjusted at any time based on 
emerging data.  Additional dosing cohorts may be added, removed, or substituted at any 
time based on emerging data and the results of continuous modelling. 


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After there is at least 1 DLT observed at any dose level, a Bayesian logistic regression 
model (BLRM) (Bailey et al, 2009; Neuenschwander et al, 2008) will be used to inform 
dose escalation and the results of this analysis will be provided to the DLRM.  
Three toxicity probability intervals (TPI) of DLT will be defined:  target TPI (20% to 30%), 
excessive TPI (30% to 60%), and unacceptable TPI (60% to 100%).  Adverse events 
meeting DLT criteria after week 4 and PD information may also be included in the model, 
as available.  The model will recommend an MTD as the dose with highest probability in 
the target TPI, but with less than 25% probability in excessive TPI and unacceptable 
TPI.  Lower dose levels, intermediate dose levels or alternative dosing schedules may 
be considered based on all available information as long as they do not exceed the 
estimated MTD per the model.  In addition, Amgen may add subjects to dose levels 
below the MTD in order to better characterize PK and PD.  After DLT is observed, the 
BLRM model will be run after each dosing cohort and may be run at any time to 
continuously update the MTD information.  For technical details of BLRM, please refer to 
Statistical Analysis Plan (SAP). 
During or after completion of the dose escalation part of the study, Amgen may enroll 
approximately 10 additional subjects in an optional dose expansion cohort in order to 
gain additional safety and efficacy information prior to the selection of an 
 dose.  
Determination of the dose for the dose expansion cohort will be based on review of all 
available information, including but not limited to BLRM model, other safety data, PK/PD, 
and efficacy.  This dose cannot exceed the model predicted MTD.  A dose that has not 
been previously explored may also be considered.  The BLRM model may be run 
anytime during the dose expansion cohort, and Amgen may change the expansion 
cohort dose level or add additional subjects for dose expansion based on emerging 
information. 
After all subjects in the phase 1b part of the study have had the opportunity to undergo 
assessment for the week 16 visit Amgen will review all the available information, 
including but not limited to the BLRM model, other safety data, PK/PD, and efficacy, to 
select the 
 
All phase 1b subjects will continue efavaleukin alfa therapy at their current dose until the 
 is established.  Subjects still receiving or planned to receive efavaleukin alfa 
treatment at the time that 
 is determined may change their efavaleukin alfa dose to 
the 
 dose at the discretion of the Sponsor, following discussion and agreement 
between the principal investigator and medical monitor, and may continue study 


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treatment through the week 260/EOET visit if they remain eligible for extended 
dosing (see Table 2-6). 
5.2 
Number of Subjects 
Approximately 40 subjects will be enrolled in phase 1b of the study, with about 
30 subjects in the dose escalation cohorts and approximately 10 subjects in the optional 
dose expansion cohort.  The total sample size may be higher than 40 subjects if, 
following a DLRM recommendation or Amgen decision to evaluate additional doses, 
dosing cohorts are added and/or existing cohorts are expanded; or if subjects are 
replaced as per Section 5.2.1.  Additional subjects may be enrolled in each cohort to 
enable all screened eligible subjects to participate in the study. 
 
Subjects in this clinical investigation shall be referred to as “subjects.” 


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5.2.1 
Replacement of Subjects 
Subjects enrolled in the phase 1b portion of the study may be replaced if they receive 
fewer than 4 doses of efavaleukin alfa prior to discontinuing study participation. 
Subjects enrolled in the 
 
 
 
5.2.2 
Number of Sites 
Approximately 14 sites in North America, Europe, and Asia will participate in the 
phase 1b portion of the study and 
 
  Sites that do not enroll subjects 
within approximately 3 months of site initiation may be closed. 
5.3 
End of Study 
5.3.1 
End of Study Definition 
Primary Completion:  The primary completion date is defined as the date when the last 
subject is assessed or receives an intervention for the final collection of data for the 
 
 
If the study concludes prior to the primary completion date originally planned in the 
protocol (ie, early termination of the study), then the primary completion will be the date 
when the last subject is assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit). 
End of Study:  The end of study date is defined as the date when the last subject 
across all sites is assessed or receives an intervention for evaluation in the study  
(ie, last subject last visit), following any additional parts in the study (eg, safety 
follow-up), as applicable. 
5.3.2 
Study Duration for Subjects 
The study will consist of up to a 28-day screening period, a 52 week treatment period 
(up to 260 weeks for subjects in phase 1b who enter the extended dosing period), and a 
6 week safety follow-up period.  The maximum duration of trial participation for an 
individual subject is approximately 14 months (up to 62 months for subjects in phase 1b 
who enter the extended dosing period) from screening through safety follow-up. 


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5.4 
Justification for Investigational Product Dose 
Based on data from Study 20160283 as of 27 October 2020, efavaleukin alfa has 
demonstrated acceptable safety and tolerability in patients with cGVHD at doses up to 
 µg Q2W administered for up to 54 weeks.  Efavaleukin alfa has also demonstrated 
pharmacodynamic selectivity with greater fold increase in the mean blood Treg counts 
compared to mean CD4 Tcon counts across all the doses and dosing frequencies tested 
although high inter-subject variability in response was observed.  The increases in CD4+ 
Tcon were minimal and demonstrated both inter-subject and inter-visit variability.  The 
observed safety profile and pharmacodynamics of efavaleukin alfa in cGVHD patients 
support further dose escalation to investigate whether higher Treg expansion can be 
achieved with continued maintenance of selectivity. 
The additional efavaleukin alfa dose of 
 µg Q2W was selected based on about 
2-fold higher predicted drug exposures than the 
 µg Q2W dose with about 9-fold 
and 1.3-fold exposure margins of AUC and Cmax relative to the NOAEL dose in the 
3-month toxicology study.  The observed exposures of efavaleukin alfa in cGVHD 
patients are approximately dose proportional.  The proposed dose of 
 µg Q2W was 
selected to minimize overlap in exposures compared to the observed exposures at the 
 µg Q2W dose (Table 3-1).  The cohort 5 dose of 
 µg Q2W is predicted to have 
good separation in exposure based on the estimated interquartile ranges (IQRs) of AUC 
and Cmax at the 
 µg Q2W dose.  
Population PK/PD modeling was performed to predict efavaleukin alfa Treg expansion in 
humans following 
 and 
 µg doses given QW and 
 and 
 µg doses 
given Q2W.  Exposure response relationships were modelled using observed 
efavaleukin alfa human exposures and pharmacodynamic outputs from cohorts 1 
through 8 (
 to 
 µg) of the SAD, FIH study in healthy subjects and all available 
PK/PD data from 3 phase 1b studies:  20170103 (up to 
 µg Q2W in subjects with 
SLE); 20170149 (up to 
 µg Q2W in subject with RA); and this study, 20160283 (up 
to 
 µg Q2W).  For each dosing frequency (QW or Q2W), predicted 
 
 
consistent with observed data.  The 
 µg Q2W dose is predicted to produce a 
roughly 30% increase in the 
 compared to the 
 µg 
Q2W dose. 


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6. 
Study Population 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening).  This log may be completed and updated via an Interactive Voice Response 
System (IVRS)/Interactive Web Response System (IWRS). 
Before any study-specific activities/procedures, the appropriate written informed consent 
must be obtained (see Appendix 3). 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions will not be provided. 
6.1 
Inclusion Criteria 
For both phase 1b and 
 subjects are eligible to be included in the study only if 
all of the following criteria apply: 
101 
Subject has provided informed consent prior to initiation of any study-specific 
activities/procedures. 
102 
Subject is an adult ≥ 18 years old at the time of signing the informed consent. 


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103 
Subject is a recipient of an allogeneic HSCT. 
104 
Subject has moderate to severe steroid-refractory cGVHD as defined by all of the 
following criteria: 

Diagnosed with cGVHD per the 2014 cGVHD NIH Consensus Criteria
(Jagasia, 2015; Appendix 8).

Steroid refractory cGVHD, defined as having persistent signs and symptoms
of cGVHD despite ≥ 4 weeks of prednisone (or equivalent) dosed at
≥ 0.25 mg/kg/day (or ≥ 0.5 mg/kg every other day).

Moderate to severe cGVHD (in accordance with 2014 cGVHD NIH
Consensus Criteria [Jagasia, 2015; Appendix 9]) at screening with
involvement of at least 1 of the following organs at the screening and
baseline visits:  skin, mouth, eyes, gastrointestinal (GI) tract, liver, lungs, and
joint and fascia.
105 
Subject has received no more than 3 previous treatments for cGVHD, excluding 
topical agents. 

Treatment with corticosteroids is considered a treatment for cGVHD and
should be included in determining the number of previous treatments.

Lines of therapy consisting of concurrent medications or interventions
(eg, tacrolimus and corticosteroids; ECP and corticosteroids) count as
2 separate treatments.

If cGVHD has worsened during a taper of immunosuppressive agents,
restoring the agents to therapeutic level is permitted and does not count as
an additional treatment.
106 
Subject may be receiving corticosteroid therapy provided that the dose is 
≤ 1 mg/kg/day of systemic prednisone or equivalent and has been stable for at 
least 2 weeks prior to first dose of efavaleukin alfa. 
107 
Subject may be receiving other non-corticosteroid immunosuppressive therapies 
provided that the immunosuppressant dose is stable for at least 2 weeks prior to 
first dose of efavaleukin alfa.  Adjustments to dose of calcineurin inhibitor or 
sirolimus are allowed only to maintain drug levels within therapeutic range. 
108 
Subject has a Karnofsky performance status score ≥ 50%. 
109 
Subject has an estimated life expectancy of > 3 months. 
110 
Subject must have adequate hepatic function, defined below, unless the treating 
physician documents the abnormal LFTs as consistent with hepatic cGVHD: 

total bilirubin < 2.0 mg/dL (34.2 µmol/L) [elevated values due to Gilbert’s
Syndrome or of non-hepatic origin are excluded].

aspartate transaminase [AST; SGOT]/Alanine transaminase [ALT; SGPT]
≤ 2x upper limit of normal (ULN).

If LFT abnormalities are deemed consistent with hepatic cGVHD by the
investigator, a liver biopsy will not be mandated.
111 
Subject must have adequate pulmonary function defined as:  forced expiratory 
volume in 1 second (FEV1) ≥ 50% or hemoglobin-adjusted diffusion capacity for 


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carbon monoxide (DLCO Hb) ≥ 40% of predicted, unless pulmonary dysfunction is 
deemed to be due to cGVHD. 
112 
Subject must have adequate renal function defined as:  a calculated glomerular 
filtration rate of > 50 mL/min/1.73 m2 using the MDRD formula. 
113 
Subject must have adequate cardiac function defined as:  no history within 
6 months prior to screening of myocardial infarction, unstable angina, New York 
Heart Associate Class III or IV heart failure, or stroke.  No findings on the 
screening electrocardiogram (ECG) that in the opinion of the investigator requires 
further cardiovascular evaluation, including severe uncontrolled ventricular 
arrhythmias, electrocardiographic evidence of acute ischemia or active 
conduction system abnormalities. 
114 
Subject must have adequate bone marrow function indicated by 
ANC > 1.00 x 109/L and platelets > 50 x 109/L without growth factors or 
transfusions within the 4 weeks prior to starting efavaleukin alfa. 
6.2 
Exclusion Criteria 
Subjects in both phase 1b and 2 are excluded from the study if any of the following 
criteria apply. 
201 
Subject is concurrently receiving treatment with calcineurin-inhibitor plus 
sirolimus (either agent alone is acceptable). 
202 
Subject has received ibrutinib, imatinib, bortezomib, entospletinib, ruxolitinib or 
other JAK inhibitor, or treatment with any investigational drug or device within 
4 weeks prior to starting efavaleukin alfa. 
203 
Subject has received treatment with T-cell depleting, B-cell depleting or IL-2 
signaling targeted medication (eg, ATG, alemtuzumab, basiliximab, denileukin 
diftitox, IL-2, rituximab) within 12 weeks prior to starting efavaleukin alfa. 
204 
Subject has received treatment with T regulatory cell expanding therapies 
(ie, PUVA, UVB, adoptively transferred T regulatory cells) within 4 weeks prior to 
starting efavaleukin alfa. 
205 
Subject has received a donor lymphocyte infusion within 12 weeks prior to 
starting dose of efavaleukin alfa. 
206 
Subject with active morphologic relapse/progression of hematologic malignancy 
post transplantation.  Persistent CLL early after transplantation that subsequently 
entered remission will not be excluded. 
207 
Subject has a history of malignancy, other than the indication for hematopoietic 
cell transplantation, with the following exceptions: 
 
adequately treated nonmelanoma skin cancers without current evidence of 
disease 
 
adequately treated cervical carcinoma in situ without current evidence of 
disease 
 
adequately treated breast ductal cancer in situ without current evidence of 
disease 


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 
any malignancy treated with curative intent and with no evidence of active 
disease present for more than 5 years prior to screening and felt to be at low 
risk for recurrence by the treating physician 
208 
Subject has a history of thrombotic microangiopathy, hemolytic-uremic syndrome 
or thrombotic thrombocytopenic purpura. 
209 
Subject has an active infection requiring treatment with intravenous antibiotics or 
has been hospitalized for treatment of an active infection in the 4 weeks prior to 
starting dose of efavaleukin alfa. 
210 
Subject has known history of active tuberculosis. 
211 
Positive test for tuberculosis during screening defined as either: 
 
positive purified derivative (PPD) (≥ 5 mm of induration at 48 to 72 hours after 
test is placed) OR 
 
positive Quantiferon or T-SPOT test 
o a positive PPD and a history of Bacillus Calmette-Guérin vaccination 
are allowed with a negative Quantiferon or T-SPOT test and negative 
chest x-ray 
o a positive PPD test (without a history of Bacillus Calmette-Guérin 
vaccination) or a positive Quantiferon or T-SPOT test are allowed if 
they have ALL of the following at screening: 
 
no symptoms per tuberculosis worksheet provided by Amgen 
 
document history of a completed course of adequate prophylaxis 
(completed treatment for latent tuberculosis per local standard of 
care prior to the start of investigational product 
 
no known exposure to a case of active tuberculosis after most 
recent prophylaxis 
 
negative chest X-ray 
o an indeterminate Quantiferon or T-SPOT test is allowed if they have 
ALL of the following at screening: 
 
no symptoms per tuberculosis worksheet provided by Amgen 
 
no known recent exposure to a case of active tuberculosis 
 
no history of a positive Quantiferon or T-SPOT test without 
documented history of a completed course of adequate 
prophylaxis (completed treatment for latent tuberculosis per local 
standard of care prior to the start of investigational product) 
 
negative chest X-ray 
 
are deemed to be at low risk for tuberculosis exposure in the 
opinion of the principle investigator 
212 
Subject is positive for hepatitis B surface antigen, hepatitis B core antibody 
(confirmed by hepatitis B deoxyribonucleic acid [DNA] polymerase chain reaction 
[PCR] test) or detectable hepatitis C virus ribonucleic acid (RNA) by PCR 
(screening is generally done by hepatitis C antibody [HepCAb], followed by 
hepatitis C virus RNA by PCR if HepCAb is positive).  Subjects with a history of 
hepatitis B vaccination without history of hepatitis B are allowed. 


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213 
Subject has positive test results for Human Immunodeficiency Virus (HIV) or 
known to be HIV-positive. 
214 
Phase 1b subject has a drug or alcohol urine test positive for illicit drugs at the 
screening visit.  Medications detected by the drug test are allowed if they are 
being taken under the direction of a physician or if permitted for recreational 
purposes as per country regulations. 
215 
Phase 1b subject cannot be a current smoker, nor have used any nicotine or 
tobacco containing products within the last 6 months prior to screening.  These 
types of products include but are not limited to:  snuff, chewing tobacco, cigars, 
cigarettes, pipes, or nicotine patches. 
216 
Phase 1b subject is unable to avoid alcohol during the 4-week DLT evaluation 
period or tobacco consumption for the duration of the study. 
217 
Subject has known sensitivity to efavaleukin alfa or its excipients to be 
administered during dosing. 
218 
Subject likely to be unable to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures (eg, Clinical 
Outcome Assessments [COAs]) to the best of the subject and investigator’s 
knowledge. 
219 
History or evidence of any other clinically significant disorder, condition, or 
disease (with the exception of those outlined above) that, in the opinion of the 
investigator or Amgen physician, if consulted, would pose a risk to subject safety 
or interfere with the study evaluation, procedures, or completion. 
220 
Females who are pregnant or breastfeeding, or planning to become pregnant or 
breastfeed during treatment and for an additional 6 weeks after the last dose of 
efavaleukin alfa. 
221 
Females of child-bearing potential with a positive pregnancy test (assessed by a 
serum pregnancy test at screening and a urine pregnancy test at baseline). 
222 
Females of childbearing potential who are unwilling to use 1 highly effective 
method of contraception during treatment and for an additional 6 weeks after 
receiving the last dose of efavaleukin alfa.  Refer to Appendix 5 for additional 
contraception information. 
223 
Subject has previously entered this study. 
6.3 
Lifestyle Restrictions 
6.3.1 
Alcohol and Tobacco (Phase 1b) 
Phase 1b subjects will be required to avoid alcohol consumption during the 4-week DLT 
evaluation period.  After the 4-week DLT evaluation period, alcohol consumption is 
strongly discouraged and is prohibited in those subjects with hepatic GVHD, underlying 
hepatic abnormalities, or elevated liver function tests at the baseline visit. 
Phase 1b subjects must not use any nicotine or tobacco containing products within 
6 months prior to screening and throughout the study.  These types of products include 
but are not limited to:  snuff, chewing tobacco, cigars, cigarettes, pipes, or nicotine 
patches. 


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6.4 
Subject Enrollment 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board/independent ethics 
committee (IRB/IEC) approval of the protocol, informed consent form, and all other 
subject information and/or recruitment material, if applicable (see Appendix 3). 
The subject must personally sign and date the IRB/IEC and Amgen approved informed 
consent before commencement of study-specific procedures. 
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria and has been enrolled via the Interactive Voice Response 
System/Interactive Web Response System (IVRS/IWRS).  The investigator is to 
document this decision and date, in the subject’s medical record and it will be transferred 
from the IVRS/IWRS to the subject’s enrollment case report form (CRF). 
Subjects will be screened to determine eligibility 28 days prior to baseline visit 
(see Table 2-1 and Table 2-7). 
Each subject who enters into the screening period for the study receives a unique 
subject identification number before any study-related activities/procedures are 
performed.  The subject identification number will be assigned using the IVRS/IWRS.  
This number will be used to identify the subject throughout the clinical study and must be 
used on all study documentation related to that subject. 
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened. 
6.5 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study 
but are not subsequently enrolled in the study.  A minimal set of screen failure 
information will be collected in the source documents that includes demography, screen 
failure details, eligibility criteria, and any serious adverse events. 
Individuals who do not meet the criteria for participation in this study (screen failure) may 
be rescreened (Section 9.1.1). 
7. 
Treatments 
Study treatment is defined as any investigational product(s), non-investigational 
product(s), placebo, or medical device(s) intended to be administered to a study subject 
according to the study protocol. 


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Note that in several countries, investigational product and non-investigational product 
are referred to as investigational medicinal product and non-investigational medicinal 
product, respectively. 
Efavaleukin alfa will be manufactured and packaged by Amgen Inc. and distributed using 
Amgen clinical study drug distribution procedures.  It is a liquid formulation presented in 
glass vials.  An Investigational Product Instruction Manual (IPIM), containing detailed 
information regarding the storage, formulation, preparation, and administration of 
investigational product will be provided separately. 
7.1 
Treatment Procedures 
7.1.1 
Investigational Products 
Table 7-1.  Study Treatments 
Study Treatment Name 
Amgen Investigational Product:   
Efavaleukin Alfa 
Dosage Formulation 
Efavaleukin alfa is a liquid formulation presented 
in glass vials 
Unit Dose Strength(s)/ 
Dosage Level(s) and Dosage Frequency 
Phase 1b 
Cohort 1:
µg biweekly 
Cohort 2
 µg weekly 
Cohort 3: 
µg biweekly 
Cohort 4
 µg weekly 
Cohort 5: 
µg biweekly 
Route of Administration 
Subcutaneous injection 
Accountability 
The amount of investigational product used in 
preparation, total volume of preparation, quantity 
administered, start date, start time, frequency, 
and lot number of efavaleukin alfa are to be 
recorded on each subject’s CRF. 
Dosing Instructions 
A qualified staff member at the site will administer 
all SC injections in the abdomen, upper arm or 
thigh.  A physician must be available at the time 
of administration of efavaleukin alfa 
Phase 1b:  Subjects will receive weekly or 
biweekly SC doses of efavaleukin alfa at the site 
administered by study personnel for the duration 
of the study.  Subjects will remain at the site for at 
least 1 hour following the first and second dose of 
efavaleukin alfa and for 30 minutes following all 
remaining doses. 


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7.1.2 
Non-investigational Products 
Non-investigational products will not be used in this study. 
7.1.3 
Medical Devices 
No investigational medical devices will be used in this study 
Other non-investigational medical devices may be used in the conduct of this study as 
part of standard care. 
Non-investigational medical devices (eg, syringes, sterile needles, and vials required for 
investigational product dilution) will be provided by Amgen.  These items will be listed 
specifically in the IPIM. 
7.1.4 
Other Protocol-required Therapies 
There are no other protocol-required therapies. 
7.1.5 
Other Treatment Procedures 
There are no other treatment procedures in this study. 
7.1.6 
Product Complaints 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug, combination product, or device after it is released for 
distribution to market or clinic by either (1) Amgen or (2) distributors or partners for 
whom Amgen manufactures the material.  This includes all components distributed 
with the drug, such as packaging drug containers, delivery systems, labeling, and 
inserts. 
This includes any drug(s), device(s) or combination product(s) provisioned and/or 
repackaged/modified by Amgen.  Drug(s) or device(s) includes investigational product.  
For this study, Amgen will collect product complaints for efavaleukin alfa. 
Any product complaint(s) associated with an investigational product(s), 
non-investigational product(s), device(s), or combination product(s) supplied by Amgen 
are to be reported according to the instructions provided in the IPIM. 
7.1.7 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
Subjects may not initiate treatment with donor lymphocyte infusions, ECP, recombinant 
IL-2 (eg, aldesleukin, ILTOO), with T-cell depleting (eg, ATG, alemtuzumab), IL-2 
signaling targeted medication (eg, basiliximab, daclizumab, denileukin dififtitox) or Treg 


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cell expanding therapies (ie, recombinant IL-2, adoptively transferred Treg cells) during 
study participation. 
7.2 
Method of Treatment Assignment 
This study includes a single arm, open-label, multiple ascending dose stage followed by 
.  Subjects will be assigned to the dose levels in the order 
described in Section 5.1.1.  In the phase 1b stage of the study, enrollment of alternating 
concurrent dosing cohorts will be facilitated by IVRS.  
 
.  The 
treatment assignment date is to be documented in the subject’s medical record and on 
the enrollment case report form (CRF). 
7.3 
Blinding 
This is an open-label study; blinding procedures are not applicable. 
7.4 
Dose Modification 
7.4.1 
Phase 1b Dose-cohort Study Escalation/De-escalation 
7.4.1.1 
Dose Level Review Meetings 
After all DLT-evaluable subjects within a cohort have completed the 4-week DLT 
evaluation period, a DLRM will be held to review data, monitor safety, and make dose 
change decisions.  See Appendix 3 for more details on the DLRM. 
7.4.1.2 
Definition of Dose Limiting Toxicities for Phase 1b 
The DLT evaluation period for each subject is 4 weeks from the first dose of efavaleukin 
alfa.  To be evaluable for a DLT subjects must have received at least 2 doses of 
efavaleukin alfa or have experienced a DLT within the DLT evaluation period.  All 
subjects who experience a DLT will discontinue study therapy and complete safety 
follow-up.  Dose limiting toxicity events will be used to guide dose escalation decisions 
and to determine the MTD as described in Section 5.1.1. 
The following DLT criteria apply only to the phase 1b part of the study: 
 
Non-hematological toxicity ≥ grade 4 related to efavaleukin alfa.  Non-hematological 
laboratory abnormalities without clinical significance will not be considered DLTs 
(based upon the investigator’s discretion in conjunction with Amgen). 
 
Hematological toxicity ≥ grade 4 related to efavaleukin alfa defined as decreases in 
peripheral counts (ANC or platelets) persisting longer than 72 hours, as measured by 
2 separate results, that are not related to malignant disease relapse, infection, or 
other etiologies. 
 
Constitutional events (ie, fever, fatigue) ≥ grade 3 that are classified as serious 
adverse events by the investigator and related to efavaleukin alfa. 


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 
Infection:  Infection is considered an expected complication of cGVHD and its 
treatment.  cGVHD itself increases the risk of infection, including life-threatening 
infection.  Therefore only grade 4 or 5 infections considered by the investigator to be 
related to efavaleukin alfa will be reviewed by the DLRM to determine whether the 
infection is considered a DLT. 
Subjects who develop an uncontrolled grade 4 life-threatening infection (eg, sepsis, 
ARDS), as assessed by the investigator, will discontinue efavaleukin alfa and remain in 
the study for safety follow-up (see Section 9.1.5). 
After completing the 4-week DLT evaluation period, phase 1b subjects will be evaluated 
by standard safety reporting. 
7.4.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
7.4.2.1 
Amgen Investigational Product:  Efavaleukin Alfa 
The reason for dose change of efavaleukin alfa is to be recorded on each subject’s CRF. 
7.4.2.1.1 
Phase 1b 
Dose adjustment of efavaleukin alfa for individual subjects is not allowed until the 
 
is determined.  The Medical Monitor should be informed of withholding of efavaleukin 
alfa for acute clinical events such as acute infection or major surgery.  Once the 
 
dose is determined, all phase 1b subjects may continue study therapy at the 
 dose 
and frequency (at the discretion of the Sponsor, following discussion and agreement 
between the principal investigator and medical monitor) and will be subject to the dose 
adjustment guidelines in Section 7.4.2.1.2.  A subject experiencing worsening of cGVHD 
that requires the addition of new immunosuppressive medication(s) at any time during 
the study or initiation of an increase in systemic corticosteroid dose above baseline after 
week 4 of the study (at the discretion of the treating investigator) will be deemed a 
treatment failure.  These subjects will discontinue treatment and will have a safety 
follow-up visit (see Section 9.1.5). 


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7.4.3 
Hepatotoxicity Stopping and Rechallenge Rules 
Elevated hepatic laboratory values may be observed in subjects with cGVHD who have 
hepatic involvement.  In the phase 1b part of the study, the Medical Monitor should be 
consulted regarding management of subjects whose abnormal hepatic laboratory values 
are, in the opinion of the Investigator, attributable to underlying cGVHD.  Subjects in the 
7.5 
Preparation/Handling/Storage/Accountability 
Guidance and information on preparation, handling, storage, accountability, destruction, 
or return of the investigational product during the study are provided in the IPIM. 
7.6 
Treatment Compliance 
Subjects will receive the SC doses of efavaleukin alfa at the research facility 
administered by qualified study personnel for the duration of the study. 
7.7 
Treatment of Overdose 
The effects of overdose of this product are not known. 


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7.8 
Prior and Concomitant Treatment 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 7.1.7. 
All other therapies including steroids, other immunosuppressive medications, 
prophylactic therapies for infections, and other medications considered supportive care 
for GVHD will not be provided or reimbursed by Amgen (except if required by local 
regulation).  The investigator will be responsible for obtaining these therapies. 
7.8.1 
Prior Treatment 
Prior therapies that were being taken from 12 weeks prior to enrollment through the 
first dose of investigational product should be collected.  Collect complete prior therapy 
history for GVHD.  For prior therapies, collect therapy name, indication, dose, unit, 
frequency, route, start date and if applicable, stop date. 
7.8.2 
Concomitant Treatment 
Concomitant therapies are to be collected from first dose of investigational product 
through safety follow-up in the source documents and the eCRF. 
For all therapies, collect therapy name, indication, dose, unit, frequency, route, start 
date, and stop date. 
7.8.2.1 
Corticosteroids 


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7.8.2.2 
Other Immunosuppressive Medications 
Subjects will continue other systemic immunosuppressive background therapies 
(eg, tacrolimus, sirolimus, MMF, ECP) concomitantly with efavaleukin alfa.  Addition or 
substitution of systemic immunosuppressive therapies beyond dose adjustments to 
maintain therapeutic levels will be considered a treatment failure.  Dose reductions in 
background therapy are not allowed in the first 8 weeks of the study but may be reduced 
thereafter in responders at the discretion of the investigator.  Disease flares during 
immunosuppressant taper will not be counted as GVHD progression or treatment failure 
if the subject can be managed by return to the baseline immunosuppressant dose.  
Topical immunosuppressant (ie, mouthwash, eye drops, genitourinary ointments) are 
allowed at the discretion of the investigator. 
7.8.2.3 
Prophylaxis for Infection 
Prophylaxis for infection, including routine viral bacterial and fungal prophylaxis 
(ie, Bactrim, acyclovir, azole fungals), will be managed according to institutional 
guidelines.  Antimicrobial treatment including antivirals, antibiotics and antifungals will be 
left to the discretion of the investigator. 
7.8.2.4 
Other Allowed Therapies 
Supportive medications in accordance with standard practice (such as emesis, diarrhea, 
red blood cell [RBC] or neutrophil growth factors) are permitted per investigator 
discretion.  Other allowed therapies include medications considered supportive care or 
prophylactic therapy for cGVHD including but not limited to ursodeoxycholic acid, INH, 
azithromycin, and montelukast. 
8. 
Discontinuation Criteria 
Subjects have the right to withdraw from investigational product and/or other 
protocol-required therapies, protocol procedures, or the study as a whole at any time 
and for any reason without prejudice to their future medical care by the physician or at 
the institution. 
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product, device, and/or other protocol-required therapies, protocol procedures, or the 
study as a whole at any time prior to study completion for the reasons listed in 
Sections 8.1, 8.2.1, and 8.2.2. 


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8.1 
Discontinuation of Study Treatment 
Subjects can decline to continue receiving investigational product and/or other 
protocol-required therapies or procedures at any time during the study but continue 
participation in the study.  If this occurs, the investigator is to discuss with the subject the 
appropriate processes for discontinuation from investigational product or other 
protocol-required therapies and must discuss with the subject the possibilities for 
continuation of the Schedule of Activities (see Table 2-1, Table 2-2, Table 2-3, 
Table 2-4, Table 2-5, Table 2-6, Table 2-7, and Table 2-8) including different options of 
follow-up (eg, in person, by phone/mail, through family/friends, in 
correspondence/communication with other treating physicians, from the review of 
medical records) and collection of data, including endpoints, adverse events, and 
disease-related events, as applicable and must document this decision in the subject’s 
medical records.  Subjects who have discontinued investigational product and/or other 
protocol-required therapies or procedures should not be automatically removed from the 
study.  Whenever safe and feasible, it is imperative that subjects remain on-study to 
ensure safety surveillance and/or collection of outcome data. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
and/or other protocol-required therapies by a separate protocol or as provided for by the 
local country’s regulatory mechanism, based on parameters consistent with Appendix 3. 
Reasons for removal from protocol-required investigational product(s) or procedural 
assessments include any of the following: 
 
Decision by Sponsor 
 
Lost to follow-up 
 
Death 
 
Ineligibility determined 
 
Protocol deviation 
 
Non-compliance  
 
Adverse event 
 
Subject request 
 
cGVHD progression 
 
Requirement for alternative therapy 
 
Protocol-specified reasons as described in Section 7.4.1.2 and Section 7.4.2.1.2 
 
Pregnancy 
8.2 
Discontinuation From the Study 


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Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publicly available data 
can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study and must document the 
subject’s decision to withdraw in the subject’s medical records. 
If a subject withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must notify Amgen accordingly (see 
Appendix 6 for further details).  Refer to the Schedule of Activities for data to be 
collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 
8.2.1 
Reasons for Removal From Washout, Run-in or Invasive Procedures 
Not applicable. 
8.2.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
 
Decision by sponsor 
 
Withdrawal of consent from study 
 
Death 
 
Lost to follow-up 
8.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 
 
The site must attempt to contact the subject and reschedule the missed visit as soon 
as possible and counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or is able to 
continue in the study. 
 
In cases in which the subject is deemed lost to follow-up, the investigator or 
designee must make every effort to regain contact with the subject (where possible, 
3 telephone calls and, if necessary, a certified letter to the subject’s last known 
mailing address or local equivalent methods).  These contact attempts are to be 
documented in the subject’s medical record. 
 
If the subject continues to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 


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 
For subjects who are lost to follow-up, the investigator can search publicly available 
records [where permitted]) to ascertain survival status.  This ensures that the data 
set(s) produced as an outcome of the study is/are as comprehensive as possible. 


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9. 
Study Assessments and Procedures 
Study procedures and their time points are summarized in the Schedule of Activities 
(see Table 2-1, Table 2-2, Table 2-3, Table 2-4, Table 2-5, Table 2-6, Table 2-7, and 
Table 2-8). 
As protocol waivers or exemptions are not allowed if an enrolled subject is subsequently 
determined to be ineligible for the study, this must be discussed with the sponsor 
immediately upon occurrence or awareness to determine if the subject is to continue or 
discontinue study treatment. 
Adherence to the study design requirements, including those specified in the Schedule 
of Activities, is essential and required for study conduct. 
9.1 
General Study Periods 
9.1.1 
Screening, Enrollment and/or Randomization 
The general study assessments and procedures will apply to subjects in both the 
phase 1b and 
 portions of the study. 
Informed consent must be obtained before completing any screening procedure or 
discontinuation of standard therapy for any disallowed therapy.  After the subject has 
signed the informed consent form, the site will register the subject in the IVRS/IWRS and 
screen the subject in order to assess eligibility for participation.  The screening window is 
up to 28 days. 
All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
If a subject has not met all eligibility criteria at the end of the screening period, the 
subject will be registered as a screen fail.  Screen fail subjects may be eligible for 
re-screening 2 times in consultation with Amgen medical monitor. 
Rescreen subjects must first be registered as screen failures in IVRS/IWRS and 
subsequently registered as rescreens.  Once the subject is registered as rescreened, a 
new 28-day screening window will begin.  Subjects will retain the same subject 
identification number assigned at the original screening.  If the rescreening period begins 
more than 28 days after the original signing of the informed consent form, all screening 
procedures, including informed consent, must be repeated. 


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9.1.2 
Treatment Period 
Visits will occur per the Schedule of Activities (see Table 2-1, Table 2-2, Table 2-3, 
Table 2-4, Table 2-5, Table 2-6, Table 2-7, and Table 2-8).  In the phase 1b part of the 
study, visits may be completed within a visit window of ± 1 day through the week 4 visit.  
After the week 4 visit, the visit window may increase to ± 3 days from the scheduled visit 
date for those phase 1b subjects on Q2W dosing and ± 2 days from the scheduled dose 
date for those subjects on QW dosing.  
 
9.1.3 
Progressive Disease Visit 
A progressive disease visit should be performed any time during the study, if the 
investigator suspects progressive disease and the subject is experiencing worsening of 
cGVHD that requires the addition of new immunosuppressive medication(s) or initiation 
of an increase in systemic corticosteroid dose above baseline after week 4 of the study.  
Efavaleukin alfa should be discontinued, followed by an end of treatment visit (see 
Section 9.1.4) and a safety follow-up visit (see Section 9.1.5). 
9.1.4 
End of Treatment 
Subjects discontinuing treatment prior to week 52 for any reason (see Section 8.1) will 
be asked to complete an End of Treatment visit within a window of ± 7 days of the next 
regularly scheduled visit after the last dose of efavaleukin alfa, consisting of all 
assessments included in the week 52 visit according to the Schedule of Activities (see 
Table 2-2).  If the End of Treatment visit for a subject occurs < 7 days after a progressive 


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disease visit, then the procedures completed at the End of Treatment visit should only 
be those NOT performed at the progressive disease visit. 
For phase 1b subjects participating in the extended dosing period, subjects discontinuing 
treatment prior to week 102 or week 103 will be asked to complete the EOET visit 
within a window of  7 days of the next regularly scheduled visit after the last 
dose of efavaleukin alfa, consisting of all assessments included in week 104 visit 
according to the Schedule of Activities (see Table 2-3).  Subjects continuing 
treatment after week 104 but discontinuing treatment before week 258 (Q2W 
dosing) or week 259 (QW dosing) will be asked to complete an EOET visit within a 
window of ± 7 days of the next regularly scheduled visit after the last dose of efavaleukin 
alfa, consisting of all assessments included in the week 260 visit according to the 
Schedule of Activities (see Table 2-6).  If the EOET visit for a subject occurs < 7 days 
after a progressive disease visit, then the procedures completed at the EOET visit 
should only be those NOT performed at the progressive disease visit. 
9.1.5 
Safety Follow-up/End of Study 
Upon completion of the treatment period or permanent discontinuation from the study 
treatment for any reason, a safety follow-up visit will be performed approximately 
6 weeks (± 3 days) after the last dose of efavaleukin alfa as described in the Schedule of 
Activities (see Table 2-1, Table 2-2, Table 2-3, Table 2-4, Table 2-5, Table 2-6, 
Table 2-7, and Table 2-8).  Women of childbearing potential will be required to complete 
a pregnancy test at this visit. 
9.2 
Description of General Study Assessments and Procedures 
The sections below provide a description of the individual study procedures for required 
time points.  These assessments apply to subjects in both phase 1b and 
 unless 
otherwise indicated. 
9.2.1 
General Assessments  
9.2.1.1 
Informed Consent 
All subjects must sign and personally date the IRB/IEC approved informed consent 
before any study-specific procedures are performed for both the phase 1b and 
 
portions of the study. 
9.2.1.2 
Demographics 
Demographic data including sex, age, race, and ethnicity will be collected in order to 
study their possible association with subject safety and treatment effectiveness.  


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Additionally, demographic data will be used to study the impact of biomarker variability 
and PK of efavaleukin alfa. 
9.2.1.3 
Medical History 
The Investigator or designee will collect complete medical and surgical history within 
5 years prior to enrollment.  Medical history will include information on the subject's 
concurrent medical conditions.  Record all findings on the medical history CRF.  In 
addition to the medical history above, cGVHD history must date back to the original 
diagnosis.  The current severity will be collected for each condition that has not resolved. 
9.2.1.4 
GVHD Staging Evaluation 
The clinician will complete the GVHD Staging Evaluation form at screening to document 
that study subjects meet the criteria for moderate-to-severe cGVHD per the 
2014 cGVHD NIH Consensus Criteria.  
 is not required for the 
Staging Evaluation.  Please see Appendix 9 for algorithm for calculation of cGVHD 
severity. 
9.2.1.5 
Physical Examination  
Physical examination will be performed as per standard of care.  Physical examination 
findings should be recorded on the appropriate CRF (eg, medical history, event). 
9.2.1.6 
Physical Measurements 
Height measurement in centimeters without shoes and weight measurement in 
kilograms and without shoes will be performed at the time points specified in the 
Schedule of Activities. 
9.2.1.7 
Substance Abuse History  
In phase 1b, obtain a detailed history of prior and/or concurrent use of alcohol, nicotine, 
and tobacco containing products. 
9.2.2 
Efficacy Assessments 
9.2.2.1 
Response Assessment:  NIH cGVHD Response Assessment  
(NIH Form A) 
All subjects in the study will have their clinical response assessed using the NIH cGVHD 
Response assessment (NIH Form A) per the 2014 cGVHD NIH Consensus Criteria 


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(2014 Response Criteria Working Group; Measurement of Therapeutic Response, 
ASBMT Web site) in accordance with the Schedule of Activities (see Table 2-1, 
Table 2-2, Table 2-3, Table 2-4, Table 2-5, Table 2-6, Table 2-7, and Table 2-8). 
Subjects will undergo repeat detailed assessment of ocular, oral, cutaneous, 
musculoskeletal, gastrointestinal, hepatic, and pulmonary systems per the 
 
 
  
 
 
.  Both standard and 
 
response assessments will be captured on the NIH cGVHD Response Assessment (NIH 
Form A). 


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9.2.3 
Safety Assessments 
Planned time points for all safety assessments are listed in the Schedule of Activities. 
9.2.3.1 
Adverse Events and Serious Adverse Events 
The method of recording, evaluating, and assessing causality of adverse events and 
serious adverse events and the procedures for completing and transmitting serious 
adverse event reports are provided in Appendix 4. 
9.2.3.1.1 
Time Period and Frequency for Collecting and Reporting Safety 
Event Information 
9.2.3.1.1.1 
Disease-related Events 
Disease-related events are defined in Appendix 4. 
The investigator is responsible for ensuring that all disease-related events observed by 
the investigator or reported by the subject that occur after the first dose of investigational 
product through the safety follow-up visit/end of study are recorded using the Event 
CRF. 
All serious disease-related events will be recorded and reported to the sponsor or 
designee within 24 hours.  The investigator will submit any updated serious disease-
related event data to the sponsor within 24 hours of it being available. 
Disease-related events assessed by the investigator to be more severe than expected 
and/or related to the investigational product(s)/study treatment/protocol-required 
therapies, and determined to be serious, must be reported on the Event CRF as serious 
adverse events and recorded and reported per Section 9.2.3.1.1.3 and Appendix 4. 
Disease-related events pre-defined for this study are listed in Appendix 11. 
9.2.3.1.1.2 
Adverse Events 
The adverse event grading scale to be used for this study will be the CTCAE 
version 4.03 and is described in Appendix 4. 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur from first dose of investigational 
product through the safety follow-up visit/EOS are reported using the Event CRF. 
9.2.3.1.1.3 
Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through safety follow-up visit/EOS are reported using the Event CRF. 


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All serious adverse events will be collected, recorded and reported to the sponsor or 
designee within 24 hours, as indicated in Appendix 4.  The investigator will submit any 
updated serious adverse event data to the sponsor within 24 hours of it being available. 
The criteria for grade 4 in the CTCAE grading scale differs from the regulatory criteria for 
serious adverse events.  It is left to the investigator’s judgment to report these grade 4 
abnormalities as serious adverse events. 
9.2.3.1.1.4 
Serious Adverse Events After the Protocol-required Reporting 
Period 
If the investigator becomes aware of serious adverse events after the protocol-
required reporting period (as defined in Section 9.2.3.1.1.3) is complete, these serious 
adverse events will be reported to Amgen (regardless of causality).  The investigator 
will report serious adverse events to Amgen within 24 hours following the investigator’s 
awareness of the event. 
Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial cases and handled accordingly based 
on relationship to investigational product.  
If further safety related data is needed to fulfill any regulatory reporting 
requirements for a reportable event, then additional information may need to be 
collected from the subject’s records after the subject ends the study. 
9.2.3.1.2 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting adverse events and/or serious 
adverse events.  Open-ended and non-leading verbal questioning of the subject is the 
preferred method to inquire about adverse event occurrence. 
9.2.3.1.3 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial adverse event/serious adverse event report, the investigator is required to 
proactively follow each subject at subsequent visits/contacts.  All adverse events and 
serious adverse events will be followed until resolution, stabilization, until the event is 
otherwise explained, or the subject is lost to follow-up (as defined in Section 8.3).  
Further information on follow-up procedures is given in Appendix 4. 
All new information for previously reported serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  If specifically 
requested, the investigator may need to provide additional follow-up information, such as 
discharge summaries, medical records, or extracts from the medical records.  


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Information provided about the serious adverse event must be consistent with that 
recorded on the Event CRF. 
9.2.3.1.4 
Regulatory Reporting Requirements for Serious Adverse Events 
If subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
Prompt notification by the investigator to the sponsor of serious adverse events is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a study treatment under clinical investigation are met.  
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation.  The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators. 
Individual safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 
An investigator who receives an individual safety report describing a serious adverse 
event or other specific safety information (eg, summary or listing of serious adverse 
events) from the sponsor will file it along with the Investigator’s Brochure and will notify 
the IRB/IEC, if appropriate according to local requirements. 
9.2.3.1.5 
Pregnancy and Lactation 
Details of all pregnancies and/or lactation in female subjects and, if indicated, female 
partners of male subjects will be collected after the start of study treatment and until 
6 weeks after receiving the last dose of Amgen investigational product. 
If a pregnancy is reported, the investigator is to inform Amgen within 24 hours of learning 
of the pregnancy and/or lactation and is to follow the procedures outlined in Appendix 5.  
Amgen Global Patient Safety will follow-up with the investigator regarding additional 
information that may be requested. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered serious adverse events. 
Further details regarding pregnancy and lactation are provided in Appendix 5. 


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9.2.3.2 
Vital Signs 
The following measurements must be performed:  Systolic/Diastolic Blood Pressure, 
Heart Rate, Respiratory Rate, and Temperature.  Subject must be in a supine position in 
a rested and calm state for at least 5 minutes before blood pressure assessments are 
conducted.  If the subject is unable to be in the supine position, the subject should be in 
most recumbent position as possible.  The position selected for a subject should be the 
same that is used throughout the study and documented on the vital sign CRF.  The 
temperature location selected for a subject should be the same that is used throughout 
the study and documented on the vital signs CRF.  Record all measurements on the vital 
signs CRF. 
9.2.3.3 
Electrocardiograms (ECGs) 
Single ECGs will be collected at screening and at time points per the Schedule of 
Activities (see Table 2-1, Table 2-2, Table 2-3, Table 2-4, Table 2-5, Table 2-6, 
Table 2-7, and Table 2-8). 
Subject must be in supine position in a rested and calm state for at least 5 minutes 
before ECG assessment is conducted.  If the subject is unable to be in the supine 
position, the subject should be in most recumbent position as possible.  ECGs should be 
performed in a standardized method prior to blood draws or other invasive procedures.  
Each ECG must include the following measurements:  QRS, QT, QTc, RR, and PR 
intervals. 
The investigator will review all ECGs.  Once signed, the original ECG tracing will be 
retained with the subject's source documents.  At the request of the sponsor, a copy of 
the original ECG will be made available to Amgen. 
Standard ECG machines should be used for all study-related ECG requirements.  In 
certain circumstances Amgen may be able to provide a standard ECG machine if a site 
is unable to provide one. 
9.2.4 
Clinical Laboratory Assessments 
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the 
Schedule of Activities (see Table 2-1, Table 2-2, Table 2-3, Table 2-4, Table 2-5, 
Table 2-6, Table 2-7, and Table 2-8) for the timing and frequency. 
The investigator is responsible for reviewing laboratory test results and recording any 
clinically relevant changes occurring during the study in the Event CRF.  The investigator 
must determine whether an abnormal value in an individual study subject represents a 


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clinically significant change from the subject’s baseline values.  In general, abnormal 
laboratory findings without clinical significance (based on the investigator's judgment) 
are not to be recorded as adverse events.  However, laboratory value changes that 
require treatment or adjustment in current therapy are considered adverse events.  
Where applicable, clinical sequelae (not the laboratory abnormality) are to be recorded 
as the adverse event. 
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the Schedule of Activities. 
9.2.4.1 
Human Immunodeficiency Virus (HIV) Status 
Human immunodeficiency virus antibody titers will be assessed as specified in the 
Schedule of Activities.  The result must be negative and will be documented in the 
source document but will not be recorded on the eCRF. 
9.2.4.2 
Hepatitis B and C Status 
The following should be followed for the determination of hepatitis B and C status: 
 
if hepatitis B and/or hepatitis C status is known to be positive by serology no 
additional laboratory testing procedures are required 
 
if hepatitis B and/or hepatitis C status is not known to be positive by serology, the 
following laboratory testing is required: 
Hepatitis B surface antigen 
 
if results are hepatitis B surface antigen positive, no additional testing is necessary 
Hepatitis B Core Antibody 
 
if results are hepatitis B core antibody positive but negative for hepatitis B surface 
antigen, additional testing is necessary for hepatitis B virus DNA by polymerase 
chain reaction 
Hepatitis C virus antibody 
 
if results are hepatitis C virus antibody positive, no additional testing is necessary. 
9.2.4.3 
Tuberculosis Testing 
All subjects must receive either a PPD, Quantiferon, or T-SPOT test at screening. 
9.2.4.3.1 
Purified Protein Derivate (PPD) 
The PPD test must be read by a trained healthcare professional 48 to 72 hours after the 
test is placed.  PPD reader must be identified on the delegation of authority for this 


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responsibility.  PPD test kits will not be provided by the sponsor and must be procured 
locally. 


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9.2.4.3.2 
Quantiferon or T-SPOT Testing 
If a subject does not receive a PPD test they must have Quantiferon or T-SPOT testing 
per Section 6.2.  If testing is performed by central laboratory then refer to the central 
laboratory manual for instructions on sample collection, processing, and shipping of 
samples. 
9.2.4.3.3 
Chest Radiograph 
Subjects with a positive PPD test without a history of Bacillus Calmette-Guerin 
vaccination or subjects with a positive or indeterminate Quantiferon or T-SPOT test will 
require a chest radiograph including posterior-anterior and lateral views performed within 
3 months before the first dose of investigational product.  The radiograph report should 
be read by a radiologist or per local requirement and the report must be reviewed by the 
investigator before enrollment of the subject. 
9.2.4.4 
Pregnancy Testing 
A high sensitive (serum) pregnancy test should be completed at screening for females of 
childbearing potential.   
Note:  Females who have undergone a bilateral tubal ligation/occlusion should have 
pregnancy testing per protocol requirements.  (If a female subject, or the partner of a 
male subject, becomes pregnant it must be reported on the Pregnancy Notification 
Worksheet, see Figure 12-2).  Refer to Appendix 5 for contraceptive requirements.  
For women of childbearing potential, additional urine pregnancy testing should be 
performed at monthly intervals during treatment with efavaleukin alfa and 6 weeks 
(± 3 days) after the last dose of protocol-required therapies.  On visits where required, 
urine pregnancy tests must be given prior to dosing with investigational product.  If a 
urine pregnancy test is positive, investigational product must be withheld; if pregnancy is 
confirmed, then investigational product must be discontinued. 
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or as required per local laws and regulations. 
9.2.4.5 
Prespecified Biomarker Assessments 
No prespecified biomarkers will be collected. 
9.2.5 
Pharmacokinetic Assessments 


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9.2.6 
Pharmacodynamic Assessments 
Lymphocyte Subsets:  Blood samples will be collected for all subjects at the time points 
indicated in the Schedule of Activities.  These samples will be used to evaluate Treg, 
Tcon, and NK cells.  Sampling time points for lymphocyte subsets may be modified 
based on emerging data. 
9.2.7 
Pharmacogenetic Assessments 
If the subject consents to the optional pharmacogenetic portion of this study, DNA 
analyses may be performed.  These optional pharmacogenetic analyses focus on 
inherited genetic variations to evaluate their possible correlation to the disease and/or 
responsiveness to the therapies used in this study.  The goals of the optional studies 
include the use of genetic markers to help in the investigation of cGVHD and/or to 
identify subjects who may have positive or negative response to investigational product 
or protocol-required therapies.  No additional samples are collected for this part of the 
study.  For subjects who consent to this/these analysis/analyses, DNA may be extracted. 
The final disposition of samples will be described in Appendix 6. 
9.2.8 
Antibody Testing Procedures 


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9.2.9 
Biomarker Development 
Biomarkers are objectively measured and evaluated indicators of normal biologic 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 
intervention.  Biomarker development can be useful in developing markers to identify 
disease subtypes, guide therapy, and/or predict disease severity. 
Amgen may attempt to develop test(s) designed to identify subjects most likely to 
respond positively or negatively to investigational product(s) (eg, Amgen or non-Amgen 
investigational product or protocol-required therapies. 
Blood samples are to be collected for biomarker development at the time points 
specified in the Schedule of Activities (see Table 2-1, Table 2-2, Table 2-3, Table 2-4, 
Table 2-5, Table 2-6, Table 2-7, and Table 2-8). 
9.2.10 
Clinical Outcome Assessments 


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9.2.11 
Other Assessments  
9.2.11.1 
Peripheral Blood Mononuclear Cell 
Blood samples will be collected for all subjects at the time points indicated in the 
Schedule of Activities (see Table 2-1 and Table 2-2) for peripheral blood mononuclear 
cell (PBMC) collection in the phase 1b part of the study.  Detailed instructions on sample 
collection, processing, and shipping will be provided in a separate manual. 
9.2.11.2 
Hospitalizations 
If a subject is hospitalized anytime during the 
 
 
 
 
10. 
Statistical Considerations 
10.1 
Sample Size Determination 
10.1.1 
Phase 1b 
Approximately 40 subjects are planned to be enrolled in the phase 1b portion of the 
study.  Approximately 30 subjects will be enrolled in dose escalation cohorts and 
approximately 10 subjects may be enrolled in optional dose expansion cohort.  The total 
sample size may be higher than 40 subjects if, following a DLRM recommendation, 
additional dosing cohorts are added and/or existing cohorts are expanded; or if subjects 
are replaced as per Section 5.2.1.  With 40 subjects receiving efavaleukin alfa, there is 
an 87% chance of detecting an adverse event with a true incidence rate of 5%.  Without 
optional dose expansion cohort (ie, with 30 subjects), the chance of detecting an 
adverse event with a true incidence rate of 5% reduces to 79%. 


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10.2 
Analysis Sets, Subgroups, and Covariates 
10.2.1 
Analysis Sets 
Phase 1b 
 
Safety Analysis Set:  The safety analysis set is defined as all subjects who have 
received at least 1 dose of efavaleukin alfa in phase 1b portion of the study.  All 
phase 1b analyses will be conducted on the safety analysis set unless noted 
otherwise. 
 
DLT Analysis Set:  The analysis of DLT will be restricted to DLT analysis set which 
consists of DLT-evaluable subjects in the phase 1b portion of the study.  The DLT 
evaluation period for each subject is 4 weeks from the first dose of efavaleukin alfa.  
To be evaluable for a DLT subjects must have received at least 2 doses of 
efavaleukin alfa or have experienced a DLT within the DLT evaluation period. 


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10.2.2 
Covariates 
No covariates will be used for this study. 
10.2.3 
Subgroups 
Subgroup analyses may be conducted for primary endpoint and selected secondary 
efficacy endpoints in 
  Subgroups may include but are not limited to age, region, 
cancer type, time from transplant, time from cGVHD diagnosis, cGVHD severity, 
radiation received (yes/no), and conditioning regimen (myeloablative versus 
non-myeloablative) as well as 
 at baseline and at 1 week. 
10.2.4 
Handling of Missing and Incomplete Data 
Please refer to Section 10.4.2.2 for discussion of missing data imputation. 
10.3 
Adaptive Design 
The adaptive design elements implemented for this study are: 
 
Bayesian logistic regression model to assist dose escalation in phase 1b 
10.4 
Statistical Analyses 
The SAP will be developed and finalized before database lock.  Below is a summary of 
the timing and methods for the planned statistical analyses.  To preserve study integrity, 
the final analysis will be conducted and reported following the end of study, as defined in 
Section 5.3.1. 
10.4.1 
Planned Analyses 
10.4.1.1 
Interim Analysis and Early Stopping Guidelines 
Phase 1b 
The interim analysis of the phase 1b part of the study will be performed after the 
last subject in the phase 1b part completes 16 weeks or early terminates.  The objective 
of this analysis is to review all the available safety, tolerability, and efficacy data and 
.  No formal 
hypothesis testing is planned in this analysis. 


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10.4.1.3 
Final Analysis 
A final analysis will be performed after the end of the study, ie, after the last subject in 
the study completes the study (including the treatment period and the safety follow-up 
period), or early terminates.  All analyses described in Section 10.4.2 based on final 
study data will be performed at this time. 
10.4.2 
Methods of Analyses 
10.4.2.1 
General Considerations 
The baseline demographics, disease characteristics, and the exposure to efavaleukin 
alfa by dose level will be summarized using descriptive statistics.  Summary descriptive 
statistics by dose level will be provided.  For categorical endpoints, the descriptive 
statistics will contain the frequency and percentage.  For continuous endpoints, the 
descriptive statistics will include the number of observations, mean, standard deviation, 
median, minimum, and maximum.  


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Statistical testing will be performed with statistical significance level of 0.025 for 1-sided 
tests, and with 0.05 statistical significance level for 2-sided tests, unless specified 
otherwise.  No multiplicity adjustment will be provided, unless specified otherwise. 


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10.4.2.2 
Efficacy Analyses 
 
Endpoint 
Statistical Analysis Methods 
Primary 
Secondary 


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Endpoint 
Statistical Analysis Methods 
Secondary 
(continued) 
Exploratory 
Will be described in the SAP finalized before database lock 
 
10.4.2.3 
Safety Analyses 
10.4.2.3.1 
Analyses of Primary Safety Endpoint(s) 
 
Endpoint 
Statistical Analysis Methods 
Primary 
Phase 1b 
The Medical Dictionary for Regulatory Activities (MedDRA 
version 20.0 or later) will be used to code all adverse events to a 
system organ class and a preferred term.  Data will be summarized as 
described in the sections below. 
 
10.4.2.3.2 
Adverse Events and Disease-related Events 
Subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class and preferred term.  Tables of fatal adverse events, serious adverse events, 
and adverse events leading to withdrawal from investigational product or other 
protocol-required therapies will also be provided.  Subject incidence of events of interest 
will also be summarized.  Subject incidence of disease-related events and fatal disease-
related events will be tabulated by system organ class and preferred term. 
10.4.2.3.3 
Laboratory Test Results 
The analyses of safety laboratory endpoints will include summary statistics at selected 
time points by dose level.  Shifts in grades of selected safety laboratory values between 
baseline and the worst on-study value will be tabulated by dose level. 
10.4.2.3.4 
Vital Signs 
The analyses of vital signs will include summary statistics at selected time points, 
post-baseline maximum/minimum and change from baseline to post-baseline 
maximum/minimum by dose level. 


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10.4.2.3.5 
Physical Measurements 
The analyses of physical measurements will include summary statistics at selected time 
points and by dose level (phase 1 only). 
10.4.2.3.6 
Electrocardiogram 
The ECG measurements will be performed as per standard of care for routine safety 
monitoring, rather than for purposes of assessment of potential QTc effect.  Since these 
evaluations may not necessarily be performed under the rigorous conditions expected to 
lead to meaningful evaluation of QTc data; summaries and statistical analyses of ECG 
measurements are not planned, and these data would not be expected to be useful for 
meta-analysis with data from other trials. 
10.4.2.3.7 
Antibody Formation 
10.4.2.3.8 
Exposure to Investigational Product 
The number of days on investigational product and the total dose of investigational 
product by each dose level will be summarized using descriptive statistics. 
10.4.2.3.9 
Exposure to Concomitant Medication 
Number and proportion of subjects receiving medications/therapies of interest will be 
summarized by preferred term or category as coded by the World Health Organization 
Drug (WHODRUG) dictionary. 
10.4.2.4 
Other Analyses 
10.4.2.4.1 
Pharmacokinetic Analysis 
Summary of 
 will be provided. 
10.4.2.4.2 
Pharmacodynamic Analysis  
 
 at selected time points will be summarized by dose level. 


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11. 
References 
Arai S; Pidala J; Pusic I, et al.  A Randomized Phase II Crossover Study of Imatinib or 
Rituximab for Cutaneous Sclerosis after Hematopoietic Cell Transplantation.  Clin Can 
Res.  2016;22(2):319-327. 
Bailey S; Neuenschwander B; Laird G; et al.  A Bayesian case study in oncology Phase 
1 combination dose-finding using logistic regression with covariates.  J Biopharm Stat.  
2009;19(3):469-484. 
Blazar BR; Murphy WJ; Abedi M.  Advances in graft-versus-host disease biology and 
therapy.  Nat Rev Immunol.  2012;12(6):443-458. 
Castela E; Le Duff F; Butori C, et al.  Effects of Low-Dose Recombinant Interleukin 2 to 
Promote T-Regulatory Cells in Alopecia Areata.  JAMA Dermatol.  2014;150(7):748-751. 
Couriel DR; Saliba R; Escalon MP; et al.  Sirolimus in combination with tacrolimus and 
corticosteroids for the treatment of resistant chronic graft-versus-host disease.  Br J 
Haematol.  2005;130:409-417. 
Cutler C; Milos D; Tim HT; et al.  Rituximab for steroid-refractory chronic graft-versus-
host disease.  Blood.  2006;108(2):756-762. 
Cutler CS; Koreth J; Ritz J.  Mechanistic approaches for prevention and treatment of 
chronic GVHD.  Blood J.  2017;129(1):22-29. 
Efavaleukin alfa (AMG 592) Investigator’s Brochure.  Thousand Oaks, CA.  Amgen Inc. 
Flowers MED; Apperley JF; van Besien K; et al.  A multicenter prospective phase 2 
randomized study of extracorporeal photopheresis for treatment of chronic 
graft-versus-host disease.  Blood.  2008;112(7):2667-2673. 
Hartemann A; Bensimon G; Payan CA; et al.Low-dose interleukin 2 in patients with type 
1 diabetes:  a phase1/2 randomised, double-blind, placebo-controlled trial.  Lancet 
Diabetes Endocrinol.  2013;1(4):295-305. 
He J; Zhang X; Wei Y, et al.  Low-dose interleukin-2 treatment selectively modulates 
CD4+ T cell subsets in patients with systemic lupus erythematosus.  Nat Med.  
2016;22(9):991-993. 
International Committee of Medical Journal Editors, Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals:  Writing and Editing for Biomedical 
Publication.  2013.  http://www.icmje.org/ 
Ito S; Bollard CM; Carlsten M; et al.  Ultra low-dose interleukin-2 promotes 
immunomodulating function of regulatory T cells and natural killer cells in healthy 
volunteers.  Mol Therapy. 2014;22(7):1388-1395. 
Jagasia MH; Greinix HT; Arora M, et al.  National Institutes of Health Consensus 
Development Project on Criteria for Clinical Trials in Chronic Graft versus Host Disease:  
I.  The 2014 Diagnosis and Staging Working Group Report.  Biol Blood Bone Marrow 
Transpl.  2015;21(3):389-401. 
Kahl C; Storer BE; Sandmaier BM, et al.  Relapse risk in patients with malignant disease 
given allogeneic cell transplantation after nonmyeloablative conditioning.  Blood.  
2007;110:2744-2748. 
Koreth J; Matsuoka K; Kim HT; et al.  Interleukin-2 and Regulatory T cells in Graft-
versus-Host Disease.  N Engl J Med.  2011;365:2055-2066. 


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Koreth J; Kim HT; Jones KT; et al.  Efficacy, durability, and response predictors of 
low-dose interleukin-2 therapy for chronic graft-versus-host disease.  Blood.  
2016;128(1):130-137. 
Lee SJ; Cook EF; Soiffer R; Antin JH.  Development and Validation of a Scale to 
Measure Symptoms of Chronic Graft-versus-Host Disease.  Biol Blood Marrow 
Transplant.  2002;8:444-452. 
Lee SJ and Flowers MED.  Recognizing and Managing Chronic Graft Versus-Host 
Disease.  Hem Am Soc Hematol Educ Program.  2008;134-141. 
Lee SJ; Wolff D; Kitko C; et al.  Measuring Therapeutic Response in Chronic Graft-
versus-host Disease.  National Institutes of Health Consensus Development Project on 
Criteria for Clinical Trials in Chronic Graft-versus-Host disease:  IV.  The 2014 Response 
Criteria Working Group Report.  Biol Blood Marrow Transplant.  2015;21:984-999. 
MacDonald KPA, Hill GR, Blazar BR.  Chronic graft-versus-host disease:  biological 
insights from pre-clinical and clinical studies.  Blood.  2017;129(1):13-21. 
Martin PJ; Storer BE; Rowley SD; et al.  Evaluation of mycophenolate mofetil for initial 
treatment of chronic graft-versus-host disease.  Blood.  2009;113(21):5074-5082. 
Miklos D, Cutler CS, Arora M, et al.  Ibrutinib for chronic graft-versus-host disease after 
failure of prior therapy.  Blood.  2017;130:2243-2250. 
Neuenschwander B; Branson M; Gsponer T.  Critical aspects of the Bayesian approach 
to phase 1 cancer trials.  Stat Med.  2008;27(13):2420-2439. 
Olivieri A; Locatelli F; Zecca M; et al.  Imatinib for refractory chronic graft-versus-host 
disease with fibrotic features.  Blood.  2009;114:709-718. 
Sadoun D, Rosenzwajg M, Jolly F, et al.  Regulatory T-Cell Responses to Low-Dose 
Interleukin-2 in HCV-Induced Vasculitis.  N Engl J Med.  2011;365:2067-2077. 
Soci G and Ritz J.  Current Issues in chronic graft-versus-host disease.  Blood.  
2014;124(3):374-384. 
Todd JA; Ferreira RC; Esposito L, et al.  Regulatory T Cell Responses in Participants 
with Type 1 diabetes after a Single Dose of Interleukin-2 :  A Non-Randomized, Open 
Label, Adaptive Dose-Finding Trial.  PLos Med.  2016;13(10):e1002139. 
Ware JE.  SF-36 health survey update.  Spine.  2000;25(24):3130-3139. 


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12. 
Appendices 


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Appendix 1.  List of Abbreviations and Definitions of Terms 
 
Abbreviation or Term 
Definition/Explanation 
ADL 
activities of daily living 
AIHA 
autoimmune hemolytic anemia 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
ANA 
anti-nuclear antibody 
ANC 
absolute neutrophil count 
ARDS 
acute respiratory distress syndrome 
AST 
aspartate transaminase 
ATG 
antithymocyte globulin 
AUC 
area under the concentration-time curve 
AUClast 
AUC from time 0 to the time of the last quantifiable sample 
AUCtau 
area under the concentration-time curve over a dosing interval 
BIL 
bilirubin 
BLRM 
Bayesian logistic regression model 
BOOP 
bronchiolitis obliterans organizing pneumonia 
BOS 
bronchiolitis obliterans syndrome 
BSA 
body surface area 
BTK 
Bruton’s tyrosine kinase 
CBC 
complete blood count 
CD 
cluster of differentiation 
CFR 
Code of Federal Regulations 
cGVHD 
chronic graft versus host disease 
CIOMS 
Council for International Organizations of Medical Sciences 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum observed concentration 
CNS 
central nervous system 
COA 
clinical outcome assessments 
CPK 
creatine phosphokinase 
CVVH 
continuous veno-venous hemofiltration 
 
 
CRF 
case report form 
CTCAE 
common terminology criteria for adverse events 
DILI 
drug-induced liver injury 
DLCO Hb 
hemoglobin-adjusted diffusion capacity for carbon monoxide 


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Abbreviation or Term 
Definition/Explanation 
DLT 
dose limiting toxicity 
DLRM 
dose level review meeting 
DLRT 
Dose Level Review Team 
DRE 
disease related event 
ECG 
electrocardiogram 
ECP 
Extra Corporeal Photophoresis 
eCRF 
electronic case report form 
eSAE 
electronic Serious Adverse Event 
EDC 
electronic data capture 
End of Study (primary 
completion) 
The primary completion date is defined as the date when the  
last subject is assessed or receives an intervention for the final 
collection of data for the 
 part primary endpoint(s),  
) for the purposes of 
conducting the primary analysis, whether the study concluded as 
planned in the protocol or was terminated early. 
End of Study (end of trial) 
The end of study date is defined as the date when the  
last subject across all sites is assessed or receives an 
intervention for evaluation in the study (ie, last subject last visit), 
following any additional parts in the study (eg, safety follow-up), 
as applicable. 
EOET 
end of extended treatment 
EOS  
End of Study, defined as the last day that protocol-specified 
procedures are conducted for an individual subject. 
EU 
European Union 
Fc 
fragment, crystallizable 
FVC 
forced vital capacity 
FEV1 
forced expiratory volume in 1 second 
 
 
FIH 
first in human 
Foxp3 
forkhead box P3 
FSH 
follicle stimulating hormone 
GCP 
good clinical practice 
GI 
gastrointestinal 
GLP 
good laboratory practice 
GU 
genitourinary 
GVHD 
graft versus host disease 
HCV 
Hepatitis C virus 
HepCAb 
hepatitis C virus ribonucleic acid 
HIPAA 
Health Insurance Portability and Accountability Act 


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Abbreviation or Term 
Definition/Explanation 
HIV 
human immunodeficiency virus 
HRT 
hormonal replacement therapy 
HSCT 
hematopoietic stem cell transplant 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
IL-2 
interleukin 2 
INH 
isoniazid 
INR 
international normalized ratio 
Interactive Voice Response 
System (IVRS) 
telecommunication technology that is linked to a central 
computer in real time as an interface to collect and process 
information   
Interactive Web Response 
System (IWRS) 
web based technology that is linked to a central computer in real 
time as an interface to collect and process information  
IP 
investigational product 
IPIM 
Investigational Product Instruction Manual 
IQR 
interquartile range 
IRB 
Institutional Review Boards 
ITP 
idiopathic thrombocytopenic purpura 
IUD 
intrauterine device 
IUS 
intrauterine hormonal-releasing system 
KM 
Kaplan-Meier 
LDH 
lactate dehydrogenase 
LKM1 
liver kidney microsomal antibody -1 
LOCF 
last observation carried forward 
LTFU 
long term follow-up 
MDRD 
modification of diet in renal disease 
MedDRA 
medical dictionary for regulatory activities 
mRNA 
messenger ribonucleic acid 
MTD 
maximum tolerated dose 
MMF 
mycophenolate mofetil 
NASH 
nonalcoholic steatohepatitis 
NCI 
National Cancer Institute 
NK cells 
natural killer cells 
NKT cells 
natural killer T cells 


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Abbreviation or Term 
Definition/Explanation 
NIH 
National Institutes of Health  
NOAEL 
no observed adverse effect level 
NRI 
nonresponder imputation 
 
 
NS 
not significant 
 
 
 
 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PD 
pharmacodynamics or progressive disease 
PFT 
pulmonary function test 
PI 
principal investigator 
PK 
pharmacokinetic 
PPD 
positive purified derivative 
POR 
proof of receipts 
 
 
PUVA 
psoralen and ultraviolet A 
RA 
rheumatoid arthritis 
RBC 
red blood cell 
 
 
RNA 
ribonucleic acid 
  
 
ROM 
range of motion 
SAD 
single ascending dose 
SAP 
statistical analysis plan 
SC 
subcutaneous 
 
 
SGOT 
serum glutamic-oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SLE 
systemic lupus erythematosus 
S/N 
signal to noise 
SOC 
standard of care 


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Abbreviation or Term 
Definition/Explanation 
Source Data 
information from an original record or certified copy of the 
original record containing patient information for use in clinical 
research.  The information may include, but is not limited to, 
clinical findings, observations, or other activities in a clinical trial 
necessary for the reconstruction and evaluation of the trial.  
Source data are contained in source documents (original records 
or certified copies).  (ICH Guideline [E6]).  Examples of source 
data include Subject identification, Randomization identification, 
and Stratification Value. 
Study day 1 
defined as the first day that protocol-specified investigational 
product(s)/protocol-required therapies is/are administered to the 
subject 
SUSAR 
suspected unexpected serious adverse reactions 
TB 
tuberculosis 
TBL 
total bilirubin 
Tcon 
conventional T cells 
Tmax 
time of maximum observed concentration 
TMA 
thrombotic microangiopathy 
TPI 
toxicity probability interval 
Teff 
T effector cells 
Treg 
regulatory T cells 
QW 
every week 
Q2W 
every 2 weeks 
ULN 
upper limit of normal 
UVB 
ultraviolet B 
 


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Appendix 2.  Clinical Laboratory Tests 
All laboratory samples will be processed and sent to the central laboratory with the 
exception of: 
 
urine pregnancy 
 
Quantiferon, which may be done by central or local laboratory 
 
T-SPOT, which may be done by local laboratory with kits provided by the sites  
 
PPD – done locally with kits provided by sites per Section 9.2.4.3.1 
 
Hepatotoxicity monitoring as per Appendix 7 
The central laboratory will be responsible for all screening and on-study serum 
chemistry, hematology, serum pregnancy, hepatitis C antibody, hepatitis B surface 
antigen and core antibody, and any other laboratory tests required.  The central 
laboratory will provide a study manual that outlines handling, labeling, and shipping 
procedures for all samples.  All blood samples will be obtained by venipuncture before 
investigational product administration.  The date and time of sample collection will be 
recorded in the source documents at the site. 
Specific analytes for serum chemistry, hematology, urinalysis, and other testing to be 
conducted on blood and urine samples are listed in Table 12-1.  Additional analyte test 
results may be reported by the local or central laboratory, in accordance with 
standard laboratory procedures (eg, components of a hematology panel). 
Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Sections 6.1 to 6.2 of the protocol. 
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 


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Table 12-1.  Analyte Listing 
Central Laboratory 
Chemistrya 
Hematologya 
Coagulationb 
Urinalysisb 
Other 
Albumin 
ALP 
ALT 
AST 
Calcium 
Corrected 
calcium 
Bicarbonate 
Direct bilirubin 
Total bilirubin 
Blood urea 
nitrogen 
Chloride 
Complete lipid 
profileb 
Creatininec 
Creatine kinase 
GGT 
Glucose 
Magnesium 
Phosphorus 
Potassium 
Total protein 
Sodium 
Coagulation 
Hematocrit 
Hemoglobin 
MCH 
Platelet count 
MCHC 
MCV 
RDW 
Reticulocytes 
Red blood cells 
White blood cells 
Differential 
• Total 
neutrophils or 
segmented 
neutrophils and 
band cells 
• Eosinophils 
• Lymphocytes 
• Basophils 
• Monocytes 
 
PT 
aPTT 
INR 
Bilirubin 
Blood 
Glucose 
Ketones 
pH 
Protein 
Specific gravity 
Urobilinogen 
Microscopic exam 
(performed at the 
discretion of the 
Investigator): 
• Bacteria 
• Casts 
• Crystals 
• Epithelial cells 
• Red blood cells 
• White blood cells 
FSHd 
Serum pregnancyb 
Quantiferone 
HIV Status  
Hepatitis B surface 
Antigen 
Hepatitis B core 
antibody 
Hepatitis C virus 
antibody 
Biomarker 
development sample 
Lymphocyte subsets 
PBMC 
Optional 
pharmacogenetics 
sample 
Urine drug/alcohol 
Local Laboratory 
Urine pregnancy 
PPD 
T-SPOT 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
GGT = gamma-glutamyl transferase; MCHC = mean corpuscular hemoglobin concentration; MCV = mean 
corpuscular volume; MDRD = Modification of Diet in Renal Disease; PK = pharmacokinetics; 
PBMC = peripheral blood mononuclear cell; RDW = red cell distribution width. 
a The screening chemistry and hematology to be collected after an 8 hour overnight fast. 
b Only at screening 
c Glomerular filtration rate will be calculated by MDRD formula 
d Can be done as a part of the clinical chemistry 
e Quantiferon testing can be done locally or by the central laboratory 


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Appendix 3.  Study Governance Considerations 
Dose Level Review Meetings 
After all dose limiting toxicity (DLT)-evaluable subjects within a cohort have completed 
the 4-week DLT evaluation period, a dose level review meeting (DLRM) will be 
conducted to review and interpret safety data for the purposes of making 
recommendations about dose-level changes and evaluating safety signals.  In addition, 
ad hoc DLRMs may be convened by the Medical Monitor at any time for review of 
emerging safety events. 
The required Dose Level Review Team (DLRT) members are the Medical Monitor, 
Global Safety Officer (GSO), and Site Investigators.  Optional non-voting Amgen 
representatives may also attend as needed at the discretion of the Medical Monitor, 
including but not limited to representatives from Study management, Biostatistics, 
Clinical Pharmacology, and Clinical Biomarkers. 
For a DLRM to occur, the Medical Monitor must be in attendance and cannot be 
represented by a voting designee or delegate.  Voting designees can be identified as 
appropriate by the GSO or Site Investigator(s).  In addition, a quorum of Site 
Investigators must attend.  A quorum is defined as greater than 50% of the participating 
investigators or their qualified designee.  The DLRM will be rescheduled if these 
requirements are not met.  A Site Investigator may identify a delegate (eg, 
Sub-investigator) who is listed in the Delegation of Authority.  If a delegate attends in 
place of a Site Investigator, the Site Investigator must provide written agreement with the 
delegate’s vote. 
The DLRT members will be responsible for dosing recommendations, which may include 
escalation to the next planned dose, adding additional cohorts, escalation to an 
intermediate dose (a dose lower than the next planned dose), de-escalation to a lower 
dose; continuation, delay, or termination of dosing; or removal, repetition or expansion of 
a cohort. 
All available study data including demographics, investigational product administration, 
medical history, concomitant medications, adverse events, electrocardiograms (ECGs), 
vital signs, and laboratory results.  All available safety data, including data collected after 
the DLT evaluation period will be included.  Data to be reviewed may be unqueried.   
DLRM voting will occur as follows.  There will be a total of 3 votes:  1 for the Medical 
Monitor, 1 for the GSO or delegate, and 1 for all of the Site Investigators or delegates 


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combined.  Regardless of how many Site Investigators there are, all of the Site 
Investigators combined will have a total of one vote decided by a majority of the 
investigators (defined as greater than or equal to 50%). 
DLRT recommendations to escalate to the next planned cohort, or to an intermediate 
cohort, must be by unanimous vote.  If the DLRT is not able to reach a unanimous 
recommendation on whether to escalate to the next planned cohort or to an intermediate 
cohort, then this should be reflected in the DLRM Memo.  Other recommendations, such 
as expanding a cohort or lowering a dose can be made by a majority vote. 
The dosing change recommendations will be documented in the DLRM Memo.  After 
receiving the DLRT recommendation, Amgen will render a final decision and will issue a 
written notification of the dose change decision to study investigators.  Amgen retains 
final decision-making authority on all dose escalation/changes. 
Dose Level Determination 
The Medical Monitor will determine if a DLRM is necessary based on the cohort status 
and all available safety data.  Recommendations to escalate to a higher dose cohort will 
only occur when the previous dose regimen(s) has (have) been found to be reasonably 
tolerated based on available study data through the last subject in a dosing cohort’s 
4-week DLT evaluation period and upon unanimous agreement of the 3 DLRM votes.  
Dosing recommendations will be made on a treatment cohort basis (not on an individual 
basis). 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with: 
 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
 
Applicable ICH Good Clinical Practice (GCP) Guidelines 
 
Applicable laws and regulations 
The protocol, protocol amendments, informed consent form, Investigator’s Brochure, and 
other relevant documents (eg, subject recruitment advertisements) must be submitted to 
an IRB/IEC by the investigator and reviewed and approved by the IRB/IEC.  A copy of 
the written approval of the protocol and informed consent form must be received by 
Amgen before recruitment of subjects into the study and shipment of Amgen 
investigational product. 


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Amgen may amend the protocol at any time.  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 that Amgen distributes to the site.  
The investigator must send a copy of the approval letter from the IRB/IEC and amended 
protocol Investigator’s Signature page to Amgen prior to implementation of the protocol 
amendment at their site. 
The investigator will be responsible for the following: 
 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
 
Obtaining annual IRB/IEC approval/renewal throughout the duration of the study.  
Copies of the investigator’s reports and the IRB/IEC continuance of approval must be 
sent to Amgen 
 
Notifying the IRB/IEC of serious adverse events occurring at the site, deviations from 
the protocol or other adverse event reports received from Amgen, in accordance with 
local procedures 
 
Overall conduct of the study at the site and adherence to requirements of Title 21 of 
the U.S. Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, and all 
other applicable local regulations 
Informed Consent Process 
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 sample 
informed consent form are to be communicated formally in writing from the Amgen Trial 
Manager to the investigator.  The written informed consent form is to be prepared in the 
language(s) of the potential patient population. 
The investigator or his/her delegated representative will explain to the subject, the aims, 
methods, anticipated benefits, and potential hazards of the study before any 
protocol-specific screening procedures or any investigational product(s) is/are 
administered, and answer all questions regarding the study. 
Subjects must be informed that their participation is voluntary.  Subjects will then be 
required to sign a statement of informed consent that meets the requirements of  
21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study 
site. 


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The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was 
obtained.  The authorized person obtaining the informed consent must also sign the 
informed consent form. 
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study unless it is a local requirement.  The 
investigator shall then inform the primary care physician.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record. 
The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician is to be documented in the subject’s medical 
records, and the informed consent form is to be signed and personally dated by the 
subject and by the person who conducted the informed consent discussion.  Subject 
withdrawal of consent or discontinuation from study treatment and/or procedures must 
also be documented in the subject’s medical records; refer to Section 8. 
Subjects must be re-consented to the most current version of the informed consent 
form(s) during their participation in the study.  
The original signed informed consent form is to be retained in accordance with 
institutional policy, and a copy of the informed consent form(s) must be provided to the 
subject. 
A subject who is rescreened is not required to sign another informed consent form if the 
rescreening occurs within 28 days from the previous informed consent form signature 
date. 
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research.  The investigator or authorized designee will 
explain to each subject the objectives of the exploratory research.  Subjects will be told 
that they are free to refuse to participate and may withdraw their specimens at any time 
and for any reason during the storage period.  A separate signature will be required to 
document a subject’s agreement to allow any remaining specimens to be used for 


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exploratory research.  Subjects who decline to participate will not provide this separate 
signature. 
Data Protection/Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen. 
Subject will be assigned a unique identifier by the sponsor.  Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred. 
On the CRF demographics page, in addition to the unique subject identification number, 
include the age at time of enrollment. 
For Serious Adverse Events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with local 
laws and regulations), and age (in accordance with local laws and regulations). 
Documents that are not submitted to Amgen (eg, signed informed consent forms) are to 
be kept in confidence by the investigator, except as described below. 
In compliance with 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 subject’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 subject to permit 
such individuals to have access to his/her study-related records, including personal 
information. 
Publication Policy 
To coordinate dissemination of data from this study, Amgen may facilitate the formation 
of a publication committee consisting of several investigators and appropriate Amgen 
staff, the governance and responsibilities of which are set forth in a Publication Charter.  
The committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff, as appropriate, as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 


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not guarantee authorship.  The criteria described below are to be met for every 
publication. 
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
International Committee of Medical Journal Editors (ICMJE) Recommendations for the 
Conduct of Reporting, Editing, and Publications of Scholarly Work in Medical Journals, 
which states: 
Authorship credit is to be based on:  (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the article 
or revising it critically for important intellectual content; (3) final approval of the version to 
be published; and (4) agreement to be accountable for all aspects of the work in 
ensuring that questions related to the accuracy or integrity of any part of the work are 
appropriately investigated and resolved.  Authors need to meet conditions 1, 2, 3, and 4. 
When a large, multicenter group has conducted the work, the group is to identify the 
individuals who accept direct responsibility for the manuscript.  These individuals must 
fully meet the criteria for authorship defined above. 
Acquisition of funding, collection of data, or general supervision of the research group, 
alone, does not justify authorship. 
All persons designated as authors must qualify for authorship, and all those who qualify 
are to be listed. 
Each author must have participated sufficiently in the work to take public responsibility 
for appropriate portions of the content. 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for review.  The Clinical Trial 
Agreement among the institution, investigator, and Amgen will detail the procedures for, 
and timing of, Amgen’s review of publications. 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of multicenter 
studies, the coordinating investigator. 


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The coordinating investigator, identified by Amgen, 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 subjects 
Data Quality Assurance 
All subject data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data, centrally or 
adjudicated data).  The investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
Clinical monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of subjects are being protected; and 
that the study is being conducted in accordance with the currently approved protocol and 
any other study agreements, ICH GCP, and all applicable regulatory requirements per 
the sponsor’s monitoring plan. 
The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing CRFs, are resolved. 
The Amgen representative(s) and regulatory authority inspectors 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 (eg, CRFs and other 
pertinent data) provided that subject confidentiality is respected. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Quality, Compliance, and Audit function (or 
designees).  Inspection of site facilities (eg, pharmacy, protocol-required therapy storage 


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areas, laboratories) and review of study-related records will occur to evaluate the study 
conduct and compliance with the protocol, ICH GCP, and applicable regulatory 
requirements. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
CRFs must be completed in English.  TRADENAMES® (if used) for concomitant 
medications may be entered in the local language.  Consult the country-specific 
language requirements. 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood. 
Source Documents 
The investigator is to 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 CRFs will be included on the Amgen Delegation of Authority Form. 
Source documents provide evidence for the existence of the subject and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator’s site. 
Source documents are original documents, data, and records from which the subject’s 
CRF 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.  Source documents may also include data captured in the 
Interactive Voice Response System (IVRS)/ Interactive Web Response System (IWRS) 
system (if used, such as subject ID and randomization number) and CRF entries if the 
CRF is the site of the original recording (ie, there is no other written or electronic record 
of data, such as paper questionnaires for a clinical outcome assessment). 
Data reported on the CRF or entered in the electronic CRF that are transcribed from 
source documents must be consistent with the source documents or the discrepancies 
must be explained.  The investigator may need to request previous medical records or 
transfer records, depending on the study.  Also, current medical records must be 
available. 
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 Amgen and/or applicable regulatory 
authorities. 


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Elements to include: 
 
Subject files containing completed CRFs, informed consent forms, and subject 
identification list 
 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the IRB/IEC 
and Amgen 
 
Investigational product-related correspondence including [Proof of Receipts (POR), 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable 
 
Non-investigational product(s), and/or medical device(s) or combination product(s) 
documentation, as applicable 
Retention of study documents will be governed by the Clinical Trial Agreement. 
Study and Site Closure 
Amgen or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable 
laws, regulations, and GCP. 
Both Amgen and the Investigator reserve the right to terminate the Investigator’s 
participation in the study according to the Clinical Trial Agreement.  The investigator is to 
notify the IRB/IEC in writing of the study’s completion or early termination and send a 
copy of the notification to Amgen. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
by an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product(s) and by what mechanism, after 
termination of the study and before the product(s) is/are available commercially. 
Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document. 


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Appendix 4.  Safety Events:  Definitions and Procedures for Recording, 
Evaluating, Follow-up and Reporting 
Definition of Disease-related Event 
Disease-related Event Definition 
 
Disease-related events are events (serious or non-serious) anticipated to occur in 
the study population due to the underlying disease.  See Appendix 11 for a list of 
disease-related events.  All serious disease-related events will be recorded and 
reported to the sponsor or designee within 24 hours. 
 
Disease-related events that would qualify as an adverse event or serious adverse 
event: 
o An event based on the underlying disease that is worse than expected as 
assessed by the investigator for the subject’s condition or if the investigator 
believes there is a causal relationship between the investigational 
product(s)/study treatment/protocol-required therapies and disease worsening, 
this must be reported as an adverse event or serious adverse event. 
 
Disease-related events that do not qualify as adverse events or serious adverse 
events:  
o An event which is part of the normal course of disease under study 
(eg, disease progression in oncology or hospitalization due to disease 
progression) is to be reported as a disease-related event. 
Definition of Adverse Event 
Adverse Event Definition 
 
An adverse event is any untoward medical occurrence in a clinical study subject 
irrespective of a causal relationship with the study treatment. 
 
Note:  An adverse event can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or 
exacerbated) temporally associated with the use of a treatment, combination 
product, medical device or procedure. 
 
Note:  Treatment-emergent adverse events will be defined in the statistical analysis 
plan (SAP). 


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Events Meeting the Adverse Event Definition 
 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, electrocardiogram [ECG], radiological scans, vital 
signs measurements), including those that worsen from baseline, that are 
considered clinically significant in the medical and scientific judgment of the 
investigator (ie, not related to progression of underlying disease). 
 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study. 
 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication.  Overdose per se will not be reported as an 
adverse event/serious adverse event unless it is an intentional overdose taken with 
possible suicidal/self-harming intent.  Such overdoses are to be reported 
regardless of sequelae. 
 
The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as adverse event or serious adverse event if they fulfill the definition of an 
adverse event or serious adverse event.  Also, “lack of efficacy” or “failure of 
expected pharmacological action” also constitutes an adverse event or serious 
adverse event. 
 
Events NOT Meeting the Adverse Event Definition 
 
Medical or surgical procedure (eg, endoscopy, appendectomy):  the condition that 
leads to the procedure is the adverse event. 
 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 


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Definition of Serious Adverse Event 
A Serious Adverse Event is defined as any untoward medical occurrence 
that, meets at least 1 of the following serious criteria: 
 
Results in death (fatal) 
 
Immediately life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which 
the subject was at 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 in-patient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting.  Complications that occur during 
hospitalization are an adverse event.  If a complication prolongs hospitalization or 
fulfills any other serious criteria, the event is serious.  When in doubt as to whether 
“hospitalization” occurred or was necessary, the adverse event is to be considered 
serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an adverse event. 
 
Results in persistent or significant disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
 
Is a congenital anomaly/birth defect 
 
Other medically important serious event 
Medical or scientific judgment is to be exercised in deciding whether serious 
adverse event reporting is appropriate in other situations such as important 
medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the subject or may require medical or surgical 
intervention to prevent 1 of the other outcomes listed in the above definition.  
These events are typically to be considered serious. 
Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 
Recording Adverse Events, Disease-related Events (if applicable), and Serious 
Adverse Events 
Adverse Event, Disease-related Event (if applicable) and Serious Adverse Event 
Recording 
 
When an adverse event, disease-related event or serious adverse event occurs, it 
is the responsibility of the investigator to review all documentation (eg, hospital 
progress notes, laboratory, and diagnostics reports) related to the event. 
 
The investigator will then record all relevant adverse event/disease-related 
event/serious adverse event information in the Event case report form (CRF). 


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o Additionally, the investigator is required to report a fatal disease-related event 
on the Event CRF. 
 
The investigator must assign the following adverse event attributes: 
o Adverse event diagnosis or syndrome(s), if known (if not known, signs or 
symptoms); 
o Dates of onset and resolution (if resolved); 
o Did the event start prior to first dose of investigational product; 
o Assessment of seriousness; 
o Severity (or toxicity defined below); 
o Assessment of relatedness to efavaleukin alfa; 
o Action taken; and 
o Outcome of event. 
 
If the severity of an adverse event changes from the date of onset to the date of 
resolution, record as a single event with the worst severity on the Event CRF. 
 
It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to the sponsor in lieu of completion of the Event CRF page. 
 
If specifically requested, the investigator may need to provide additional follow-up 
information, such as discharge summaries, medical records, or extracts from the 
medical records.  In this case, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records before 
submission to the sponsor. 
 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the adverse event/serious 
adverse event. 


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Evaluating Adverse Events and Serious Adverse Events 
Assessment of Severity 
The investigator will make an assessment of severity for each adverse event and 
serious adverse event reported during the study.  The assessment of severity will be 
based on: 
The Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 which is 
available at the following location:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
Assessment of Causality 
 
The investigator is obligated to assess the relationship between investigational 
product and/or study-mandated procedure and each occurrence of each adverse 
event/serious adverse event. 
 
Relatedness means that there are facts or reasons to support a relationship 
between investigational product and the event. 
 
The investigator will use clinical judgment to determine the relationship. 
 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated. 
 
The investigator will also consult the Investigator’s Brochure and/or Product 
Information, for marketed products, in his/her assessment. 
 
For each adverse event/serious adverse event, the investigator must document in 
the medical notes that he/she has reviewed the adverse event/serious adverse 
event and has provided an assessment of causality. 
 
There may be situations in which a serious adverse event has occurred and the 
investigator has minimal information to include in the initial report.  However, it is 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the serious adverse event data. 
 
The investigator may change his/her opinion of causality in light of follow-up 
information and send a serious adverse event follow-up report with the updated 
causality assessment. 
 
The causality assessment is 1 of the criteria used when determining regulatory 
reporting requirements. 
 


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Follow-up of Adverse Event and Serious Adverse Event 
 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by 
Amgen to elucidate the nature and/or causality of the adverse event or serious 
adverse event as fully as possible.  This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health 
care professionals. 
 
If a subject is permanently withdrawn from protocol-required therapies because of 
a serious adverse event, this information must be submitted to Amgen. 
 
If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide Amgen with a copy of any post-mortem findings 
including histopathology. 
 
New or updated information will be recorded in the originally completed Event 
CRF. 
 
The investigator will submit any updated serious adverse event data to Amgen 
within 24 hours of receipt of the information. 
Reporting of Serious Adverse Event 
Serious Adverse Event Reporting via Electronic Data Collection Tool 
 
The primary mechanism for reporting serious adverse event will be the electronic 
data capture (EDC) system.  
 
If the EDC system is unavailable for more than 24 hours, then the site will report 
the information to Amgen using a paper-based electronic Serious Adverse Event 
(eSAE) Contingency Report Form (see Figure 12-1) within 24 hours of the 
investigator’s knowledge of the event. 
 
The site will enter the serious adverse event data into the electronic system as 
soon as it becomes available. 
 
After the study is completed at a given site, the EDC system will be taken off-line to 
prevent the entry of new data or changes to existing data. 
 
If a site receives a report of a new serious adverse event from a study subject or 
receives updated data on a previously reported serious adverse event after the 
EDC system has been taken off-line, then the site can report this information on 
the paper-based Serious Adverse Event Contingency Report Form (see 
Figure 12-1). 
 
Once the study has ended, serious adverse event(s) should be reported to Amgen 
(regardless of causality) if the investigator becomes aware of a serious adverse 
event.  The investigator should use the paper-based Serious Adverse Event 
Contingency Report Form to report the event. 


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Figure 12-1.  Sample Electronic Serious Adverse Event Contingency Form 


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Appendix 5.  Contraceptive Guidance and Collection of Pregnancy and Lactation 
Information 
Study-specific contraception requirements for females of childbearing potential are 
outlined in Section 6.2. 
Female subjects of childbearing potential must receive pregnancy prevention counseling 
and be advised of the risk to the fetus if they become pregnant during treatment and 
after the last dose of protocol-required therapies. 
Definition of Females of Childbearing Potential 
A female is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile.  Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy. 
Females in the following categories are not considered female of childbearing potential: 
 
Premenopausal female with 1 of the following: 
 
Documented hysterectomy; 
 
Documented bilateral salpingectomy; or 
 
Documented bilateral oophorectomy. 
Note:  Site personnel documentation from the following sources is acceptable:  
1) review of subject’s medical records; 2) subject’s medical examination; or 
3) subject’s medical history interview. 
 
Premenarchal female 
 
Postmenopausal female 
 
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT).  However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 
 
Females on HRT and whose menopausal status is in doubt will be required to 
use 1 of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study.  Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment 


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Contraception Methods for Female Subjects 
Highly Effective Contraceptive Methods 
Note:  Failure rate of < 1% per year when used consistently and correctly. 
 
Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, or transdermal) 
 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, implantable) 
 
Intrauterine device (IUD) 
 
Intrauterine hormonal-releasing system (IUS) 
 
Bilateral tubal ligation/occlusion 
 
Vasectomized partner (provided that partner is the sole sexual partner of the 
female subject of childbearing potential and that the vasectomized partner has 
received medical assessment of the surgical success) 
 
Sexual abstinence (defined as refraining from heterosexual intercourse during 
the entire period of risk associated with the study treatments; the reliability of 
sexual abstinence must be evaluated in relation to the duration of the trial and 
the preferred and usual lifestyle of the subject) 
Unacceptable Methods of Birth Control for Female Subjects 
Birth control methods that are considered unacceptable in clinical trials include: 
 
Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
 
Withdrawal (coitus interruptus) 
 
Spermicides only 
 
Lactational amenorrhoea method 
Collection of Pregnancy Information 
Female Subjects Who Become Pregnant 
 
Investigator will collect pregnancy information on any female subject who becomes 
pregnant while taking protocol-required therapies through 6 weeks. 
 
Information will be recorded on the Pregnancy Notification Worksheet (see 
Figure 12-2).  The worksheet must be submitted to Amgen Global Patient Safety 
within 24 hours of learning of a subject’s pregnancy.  (Note:  Sites are not required 
to provide any information on the Pregnancy Notification Worksheet that violates the 
country or regions local privacy laws.) 
 
After obtaining the female subject’s signed authorization for release of pregnancy 
and infant health information, the investigator will collect pregnancy and infant 
health information and complete the pregnancy questionnaire for any female subject 
who becomes pregnant while taking protocol-required therapies through 6 weeks of 
the study drug.  This information will be forwarded to Amgen Global Patient Safety.  
Generally, infant follow-up will be conducted up to 12 months after the birth of the 
child (if applicable). 


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 
Any termination of pregnancy will be reported to Amgen Global Patient Safety, 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure.  
 
While pregnancy itself is not considered to be an adverse event or serious adverse 
event, any pregnancy complication or report of a congenital anomaly or 
developmental delay, fetal death, or suspected adverse reactions in the neonate will 
be reported as an adverse event or serious adverse event.  Note that an elective 
termination with no information on a fetal congenital malformation or maternal 
complication is generally not considered an adverse event, but still must be reported 
to Amgen as a pregnancy exposure case. 
 
If the outcome of the pregnancy meets a criterion for immediate classification as a 
serious adverse event (eg, female subject experiences a spontaneous abortion, 
stillbirth, or neonatal death or there is a fetal or neonatal congenital anomaly) the 
investigator will report the event as a serious adverse event. 
 
Any serious adverse event occurring as a result of a post-study pregnancy which is 
considered reasonably related to the study treatment by the investigator, will be 
reported to Amgen Global Patient Safety as described in Appendix 4.  While the 
investigator is not obligated to actively seek this information in former study 
subjects, he or she may learn of a serious adverse event through spontaneous 
reporting.  
 
Any female subject who becomes pregnant while participating will discontinue study 
treatment (see Section 8.1 for details). 
Collection of Lactation Information 
 
Investigator will collect lactation information on any female subject who breastfeeds 
while taking protocol-required therapies through 6 weeks. 
 
Information will be recorded on the Lactation Notification Worksheet (see below) 
and submitted to Amgen Global Patient Safety within 24 hours of the investigator’s 
knowledge of event. 
 
Study treatment will be discontinued if female subject breastfeeds during the study 
as described in exclusion criterion 220. 
 
With the female subjects signed authorization for release of mother and infant 
health information, the investigator will collect mother and infant health information 
and complete the lactation questionnaire on any female subject who breastfeeds 
while taking protocol-required therapies through 6 weeks after discontinuing 
protocol-required therapies. 


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Figure 12-2.  Pregnancy and Lactation Notification Worksheet 
 


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Appendix 6.  Sample Storage and Destruction 
Any blood sample collected according to the Schedule of Activities (see Table 2-1, 
Table 2-2, Table 2-3, Table 2-4, Table 2-5, Table 2-6, Table 2-7, and Table 2-8) can be 
analyzed for any of the tests outlined in the protocol and for any tests necessary to 
minimize risks to study subjects.  This includes testing to ensure analytical methods 
produce reliable and valid data throughout the course of the study.  This can also 
include, but is not limited to, investigation of unexpected results, incurred sample 
reanalysis, and analyses for method transfer and comparability. 
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality. 
If informed consent is provided by the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand the 
dose response and/or prediction of response to efavaleukin alfa, and characterize 
aspects of the molecule (eg, mechanism of action/target, metabolites).  Results from this 
analysis are to be documented and maintained, but are not necessarily reported as part 
of this study.  Samples can be retained for up to 20 years. 
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of pharmacogenetic, [biomarker development,] or other 
exploratory studies are not placed in the subject’s medical record and are not to be 
made available to the subject, members of the family, the personal physician, or other 
third parties, except as specified in the informed consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
[sample types (eg, blood, tumor)] samples and any other components from the cells can 
be located and destroyed.  Samples will be destroyed once all protocol-defined 
procedures are completed.  However, information collected from samples prior to the 
request for destruction, will be retained by Amgen. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 


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appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  See  
Appendix 3 for subject confidentiality. 


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Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions and Follow-up 
Assessments and Study Treatment Rechallenge Guidelines 
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], 
aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBL]) 
and/or international normalized ratio (INR) and/or signs/symptoms of hepatitis (as 
described below) may meet the criteria for withholding or permanent discontinuation of 
Amgen investigational product or other protocol-required therapies, as specified in the 
Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical Evaluation, 
July 2009. 
Criteria for Withholding and/or Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required Therapies Due to 
Potential Hepatotoxicity 
The following stopping and/or withholding rules apply to subjects for whom another 
cause of their changes in liver biomarkers (TBL, INR and transaminases) has not been 
identified.  
Important alternative causes for elevated AST/ALT and/or TBL values include, but are 
not limited to: 
 
GVHD 
 
Hepatobiliary tract disease 
 
Viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, herpes 
simplex virus, varicella, and parvovirus) 
 
Protozoal infections (eg, toxoplasmosis, schistosomiasis) 
 
Right sided heart failure, hypotension or any cause of hypoxia to the liver causing 
ischemia 
 
Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary 
supplements, plants and mushrooms 
 
Heritable disorders causing impaired glucuronidation (eg, Gilbert’s syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (eg, indinavir, 
atazanavir) 
 
Alpha-one antitrypsin deficiency 
 
Alcoholic hepatitis 
 
Autoimmune hepatitis 
 
Wilson’s disease and hemochromatosis 
 
Nonalcoholic fatty liver disease including steatohepatitis (NASH) 
 
Non-hepatic causes (eg, rhabdomyolysis, hemolysis) 


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If investigational product(s) is/are withheld, the subject is to be followed for possible DILI 
according to recommendations in the last section of this appendix.  
Rechallenge may be considered if an alternative cause for impaired liver tests (ALT, 
AST, ALP) and/or elevated TBL, is discovered and the laboratory abnormalities resolve 
to normal or baseline (see next section in this appendix). 
Table 12-2.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required Therapies Due to 
Potential Hepatotoxicity 
Analyte 
Temporary Withholding 
Permanent Discontinuation 
TBL 
> 3x ULN  
at any time 
> 2x ULN 
 
 
OR 
INR 
-- 
> 1.5x ULN (for subjects not on 
anticoagulation therapy) 
 
OR 
AND 
AST/ALT 
> 8x ULN at any time 
> 5x ULN but < 8x ULN for ≥ 2 weeks 
> 5x ULN but < 8x ULN and unable to 
adhere to enhanced monitoring schedule 
> 3x ULN with clinical signs or symptoms 
that are consistent with hepatitis (such as 
right upper quadrant pain/tenderness, 
fever, nausea, vomiting, and jaundice) 
In the presence of no important 
alternative causes for elevated 
AST/ALT and/or TBL values 
> 3x ULN (when baseline was < ULN) 
 
OR 
 
ALP 
> 8x ULN at any time 
-- 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
INR = international normalized ratio; TBL = total bilirubin; ULN = upper limit of normal 
Criteria for Rechallenge of Amgen Investigational Product and Other 
Protocol-required Therapies After Potential Hepatotoxicity 
The decision to rechallenge the subject is to be discussed and agreed upon 
unanimously by the subject, investigator, and Amgen. 
If signs or symptoms recur with rechallenge, then efavaleukin alfa is to be permanently 
discontinued.  Subjects who clearly meet the criteria for permanent discontinuation (as 
described in Table 12-2) are never to be rechallenged. 


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Drug-induced Liver Injury Reporting and Additional Assessments 
Reporting 
To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST or ALT 
and TBL and/or INR elevation, according to the criteria specified in the above, require 
the following: 
 
The event is to be reported to Amgen as a serious adverse event within 24 hours of 
discovery or notification of the event (ie, before additional etiologic investigations 
have been concluded) 
 
The appropriate CRF (eg, Event CRF) that captures information necessary to 
facilitate the evaluation of treatment-emergent liver abnormalities is to be completed 
and sent to Amgen  
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Appendix 4. 
Additional Clinical Assessments and Observation 
All subjects in whom investigational product(s) or protocol-required therapies is/are 
withheld (either permanently or conditionally) due to potential DILI as specified in  
Table 12-2 or who experience AST or ALT elevations > 3 x upper limit of normal (ULN) 
or 2-fold increases above baseline values for subjects with elevated values before drug 
are to undergo a period of “close observation” until abnormalities return to normal or to 
the subject’s baseline levels.   
Additional laboratory assessments for hepatotoxicity monitoring will be performed locally. 
Assessments that are to be performed during this period include:  
 
Repeat AST, ALT, ALP, bilirubin (total and direct), and INR within 24 hours  
 
In cases of TBL > 2x ULN or INR > 1.5, retesting of liver tests, BIL (total and direct), 
and INR is to be performed every 24 hours until laboratory abnormalities improve 
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the investigational product(s) or protocol-required therapies has/have been 
discontinued AND the subject is asymptomatic. 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated TBL.  
The following are to be considered depending on the clinical situation: 
 
Complete blood count (CBC) with differential to assess for eosinophilia 
 
Serum total immunoglobulin IgG, anti-nuclear antibody (ANA), anti smooth muscle 
antibody, and liver kidney microsomal antibody -1 (LKM1) to assess for autoimmune 
hepatitis 


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 
Serum acetaminophen (paracetamol) levels 
 
A more detailed history of:  
 
Prior and/or concurrent diseases or illness 
 
Exposure to environmental and/or industrial chemical agents  
 
Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
 
Prior and/or concurrent use of alcohol, recreational drugs and special diets 
 
Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
 
Viral serologies 
 
Creatine phosphokinase (CPK), haptoglobin, lactate dehydrogenase (LDH), and 
peripheral blood smear 
 
Appropriate liver imaging if clinically indicated 
 
Appropriate blood sampling for pharmacokinetic analysis if this has not already been 
collected 
 
Hepatology consult (liver biopsy may be considered in consultation with a 
hepatologist) 
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal or considered stable by the investigator.  The 
“close observation period” is to continue for a minimum of 4 weeks after discontinuation 
of all investigational product(s) and protocol-required therapies. 
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in the corresponding CRFs. 


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Appendix 8.  NIH Defined Diagnostic or Distinctive Features of Chronic GVHD 
 
Organ or site 
Diagnostic 
(sufficient to 
Establish the 
Diagnosis of 
Chronic 
GVHD) 
Distinctivea (Seen 
in Chronic GVHD, 
but insufficient 
Alone to Establish 
a Diagnosis of 
Chronic GVHD) 
Other Features or 
Unclassified 
Entitiesb 
Commonc 
(Seen with 
Both Acute 
and Chronic 
GVHD) 
Skin 
Poikiloderma 
Lichen planus-
like features 
Sclerotic 
features 
Morphea-like 
features 
Lichen 
sclerosus-like 
features 
Depigmentation 
Papulosquamous 
lesions 
Sweat impairment 
Ichthyosis 
Keratosis pilaris 
Hypopigmentation 
Hyperpigmentation 
Erythema 
Maculopapular 
rash 
Pruritus 
Nails 
- 
Dystrophy 
Longitudinal 
ridging, splitting, or 
brittle features 
Onycholysis 
Pterygium unguis 
Nail loss (usually 
symmetric; affects 
most nails)b 
- 
- 
Scalp and 
body hair 
- 
New onset of 
scarring or 
nonscarring scalp 
alopecia (after 
recovery from 
chemoradiotherapy) 
Loss of body hair 
Scaling 
Thinning scalp hair, 
typically patchy, 
coarse, or dull (not 
explained by 
endocrine or other 
causes) 
Premature gray hair 
- 
Mouth 
Lichen-type 
features 
 
Xerostomia 
Mucocele 
Mucosal atrophy 
Ulcers 
Pseudomembranes 
- 
Gingivitis 
Mucositis 
Erythema 
Pain 
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Organ or site 
Diagnostic 
(sufficient to 
Establish the 
Diagnosis of 
Chronic 
GVHD) 
Distinctivea (Seen 
in Chronic GVHD, 
but insufficient 
Alone to Establish 
a Diagnosis of 
Chronic GVHD) 
Other Features or 
Unclassified 
Entitiesb 
Commonc 
(Seen with 
Both Acute 
and Chronic 
GVHD) 
Eyes 
- 
New onset dry, 
gritty, or painful 
eyes 
Cicatricial 
conjunctivitis 
Keratoconjunctivitis 
sicca 
Confluent areas of 
punctate 
keratopathy 
Photophobia 
Periorbital 
hyperpigmentation 
Blepharitis 
(erythema of the 
eyelids with edema) 
- 
Genitalia 
Lichen planus-
like features 
Lichen 
sclerosus-like 
features 
 
Females 
Vaginal 
scarring or 
clitoral/labial 
agglutination 
 
Males 
Phimosis or 
urethral/meatus 
scarring or 
stenosis 
Erosions 
Fissures 
Ulcers 
- 
- 
GI Tract 
Esophageal 
web 
Strictures or 
stenosis in the 
upper to mid 
third of the 
esophagus 
- 
Exocrine pancreatic 
insufficiency 
Anorexia 
Nausea 
Vomiting 
Diarrhea 
Weight loss 
Failure to 
thrive (infants 
and children) 
Liver 
- 
- 
- 
Total bilirubin, 
alkaline 
phosphatase 
> 2 x ULN 
ALT or AST 
> 2 x ULN 
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Organ or site 
Diagnostic 
(sufficient to 
Establish the 
Diagnosis of 
Chronic 
GVHD) 
Distinctivea (Seen 
in Chronic GVHD, 
but insufficient 
Alone to Establish 
a Diagnosis of 
Chronic GVHD) 
Other Features or 
Unclassified 
Entitiesb 
Commonc 
(Seen with 
Both Acute 
and Chronic 
GVHD) 
Lung 
Bronchiolitis 
obliterans 
diagnosed with 
lung biopsy 
Bronchiolans 
obliterans 
syndrome 
(BOS)d 
Air trapping and 
bronchiectasis on 
chest CT 
Cryptogenic 
organizing 
pneumonia (COP)e 
Restrictive lung 
diseasee 
 
Muscles, 
fascia, joints 
Fasciitis  
Joint stiffness 
or contractures 
secondary to 
sclerosis 
Myositis or 
polymyositisf 
Edema 
Muscle cramps 
Arthralgia or 
arthritis 
- 
Hematopoietic 
and immune 
- 
- 
Thrombocytopenia 
Eosinophilia 
Lymphopenia 
Hypo- or hyper-
gammaglobulinemia 
Autoantibodies 
(AIHA and ITP) 
Raynaud’s 
phenomenon 
- 
Other 
- 
- 
Pericardial or 
pleural effusions 
Ascites 
Peripheral 
neuropathy 
Nephrotic syndrome 
Myasthenia gravis 
Cardiac conduction 
abnormality or 
cardiomyopathy 
- 
Page 3 of 3 
a In all cases, infection, drug effect, malignancy, or other causes must be excluded. 
b Can be acknowledged as part of the chronic GVHD manifestations if diagnosis is confirmed. 
c Common refers to shared features by both acute and chronic GVHD. 
d BOS can be diagnostic for lung chronic GVHD only, if distinctive sign or symptom present in another 
organ. 
e Pulmonary entities under investigation or unclassified. 
f Diagnosis of chronic GVHD requires biopsy. 
Source:  Jagasia et al, 2015 


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Appendix 9.  NIH Global Severity of cGVHD 
Mild chronic GVHD 
1 or 2 organs involved with no more than score 1  
AND 
Lung Score 0 
Moderate chronic 
GVHD 
3 or more organs involved with no more than score 1  
OR 
At least 1 organ (not lung) with a score of 2 
OR 
Lung score 1 
Severe chronic GVHD 
At least 1 organ with a score of 3 
OR 
Lung score of 2 or 3 
Key Points: 
In skin:  higher of the 2 scores to be used for calculating global severity. 
In lung:  FEV1 is used instead of clinical score for calculating global severity 
If the entire abnormality in an organ is noted to be unequivocally explained by a 
non-GVHD documented cause, that organ is not included for calculation of the global 
severity. 
If the abnormality in an organ is attributed to multifactorial causes (GVHD plus other 
causes) the scored organ will be used for calculation of the global severity regardless 
of the contributing causes (no downgrading of organ severity score). 
Source:  Jagasia et al, 2015 


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Appendix 11.  Disease Related Events Table 
Below is a list of common Disease-Related Events.  This list is not meant to be 
comprehensive.  All serious disease-related events will be recorded and reported to the 
sponsor or designee within 24 hours. 
Organ System 
Disease Related Event 
Skin 
Scleroderma (superficial or fasciitis), lichen 
planus, vitiligo, scarring alopecia, 
hyperkeratosis pilaris, contractures from skin 
immobility, nail bed dysplasia 
Mucous membranes 
Lichen planus, non-infectious ulcers, corneal 
erosions/non-infectious conjunctivitis, 
xerostomia, keroconjunctivitis sicca 
GI tract 
Esophageal strictures, steatorrhea, anorexia, 
malabsorption, weight loss, abdominal pain 
Liver 
None  
GU tract 
Vaginal stricture, lichen planus  
Musculoskeletal /Serosa 
Non-septic arthritis, myositis, myasthenia, 
polyserositis, contractures from joint 
immobilization 
Hematologic 
None 
Lung 
Bronchiolitis obliterans 
 


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Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 5 
Protocol Title:  A Phase 1b/2 Open-label Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics, and Efficacy of Efavaleukin Alfa in Adult 
Subjects With Steroid Refractory Chronic Graft Versus Host Disease 
 
Amgen Protocol Number efavaleukin alfa 20160283 
 
Amendment Date: 
22 June 2021 
 
Rationale: 
The rationale for this protocol amendment is: 
 
To update the phase 1b part of the study to allow for continued access to 
efavaleukin alfa for up to an additional 156 weeks following week 102 (Q2W 
dose) or week 103 (QW dose) at the discretion of the Sponsor, following 
discussion and agreement between the principal investigator and medical 
monitor, for subjects who are responding to efavaleukin alfa (as assessed by 
week 104) and who wish to continue on treatment. 
 
Administrative and editorial updates. 
 


Product:  Efavaleukin Alfa 
Protocol Number:  20160283 
Date:  08 December 2020 
Page 1 of 2 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 4 
Protocol Title:  A Phase 1b/2 Open-label Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics, and Efficacy of Efavaleukin Alfa in Adult 
Subjects With Steroid Refractory Chronic Graft versus Host Disease 
 
Amgen Protocol Number efavaleukin alfa 20160283 
 
Amendment Date: 
08 December 2020 
 
Summary of Changes: 
 
Add cohort 5 (
 g every 2 weeks) for the purpose of exploring the safety, 
pharmacokinetics (PK), pharmacodynamics (PD) of higher efavaleukin alfa 
(AMG 592) doses in patients with steroid refractory chronic graft versus host 
disease.  The highest doses tested to date, 
 g every 2 weeks and 
 g 
every week, were determined at a dose level review meeting to have acceptable 
safety in this patient population.  The following changes were made: 
 
Include description of cohort 5 and enrollment to cohort 5 to study design 
 
Remove statement that efavaleukin alfa dose level not to exceed 
 g weekly 
since this statement is no longer applicable 
 
Update study schema phase 1b to include cohort 5 
 
Increase the sample size from up to 34 subjects to approximately 40 subjects 
sample size to reflect the addition of cohort 5 
 
Update human exposure and justification for investigational product dose 
sections (Section 3.2.2.2 and Section 5.4) to support the cohort 5 dose 
 
Change name of investigational product from AMG 592 to efavaleukin alfa 
 
Edit a secondary 
 
 
Consolidate risk assessment section and note that serious hypersensitivity reactions 
to efavaleukin alfa have been reported 
 
Remove timing window for National Institutes of Health (NIH) Form A for week 16 
footnote since no longer applicable (Table 2-2) 
 
Add footnote to clarify that the 2 or 6 minute walk test is optional for the NIH Form A 
assessment to 
schedule of activities 
 
Update timing windows for immunogenicity and biomarker blood sample collection 
 
Update visit window for treatment period 


Product:  Efavaleukin Alfa 
Protocol Number:  20160283 
Date:  08 December 2020 
Page 2 of 2 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
 
Remove the following assessments from the schedule of activities:  
 
Update and consolidate clinical experience information 
 
Updates to maintain consistency regarding criteria for the progressive disease visit 
 
Add permission for recreational drug use as per country regulations to exclusion 
criterion 214 
 
Clarify that the medical monitor is to be informed when efavaleukin alfa is withheld 
for acute clinical events 
 
Minor corrections to statistical considerations section to provide additional clarity 
including: 
 
Clarify that improvement of 20 is equivalent to absolute improvement of 20 in 
the sample size section 
 
Include the test used in EAST 6.4 for sample size calculation 
 
Establish analyses to be performed as part of the final analysis 
 
Move 
 from secondary efficacy endpoints to a 
new section (other analyses) 
 
Add summary of subject incidence of events of interest to analyses of adverse 
events and disease-related events 
 
Add post-baseline maximum/minimum and change from baseline to 
post-baseline maximum/minimum and remove tabulation of shifts in selected vital 
sign values between baseline and the worst on-study value to analyses of vital 
signs. 
 
Add summary of signal to noise (S/N) ratio for subjects who develop 
to analyses of antibody formation 
 
Remove summary of proportion of subjects receiving each dose level (phase 1b 
only) from the analyses of exposure to investigation product.  Remove plan to 
provide subject-level data instead of the summary if the subject incidence is low 
or single dose is given to analyses of exposure to investigation product 
 
Clarify that concomitant medication will include medications and therapies 
 
Editorial updates 
 
Provide more details for serious adverse event reporting via the electronic data 
collection tool 
 
Clarify that the disease-related events table presented in Appendix 11 is not inclusive 
 
Administrative and editorial updates 


Product:  AMG 592 
Protocol Number:  20160283 
Date:  26 August 2019 
Page 1 of 26 
CONFIDENTIAL 
 
 
Amendment 3 
Protocol Title:  A Phase 1b/2 Open-label Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics, and Efficacy of AMG 592 in Adult Subjects 
With Steroid Refractory Chronic Graft Versus Host Disease 
 
Amgen Protocol Number:  AMG 592 20160283 
 
Amendment Date: 
26 August 2019 
Rationale: 
The rationale for this protocol amendment is: 
 
To update the phase 1b part of the study to allow for continued access to 
AMG 592 for up to an additional 52 weeks following week 50 (Q2W dose) or 
week 51 (QW dose) at the discretion of the Sponsor, following discussion and 
agreement between the principal investigator and medical monitor, for subjects 
who are responding to AMG 592 (as assessed by week 50) and who wish to 
continue on treatment. 
 
To clarify that phase 1b subjects still receiving or planned to receive AMG 592 
treatment at the time that the 
 is established may change their AMG 592 
dose to the 
 dose at the discretion of the Sponsor, following discussion and 
agreement between the principal investigator and medical monitor, and may 
continue study treatment until completion of the week104/EOT visit. 
 
To correct inconsistencies in the Schedules of Assessments for the phase 1b 
part of the study with regard to corticosteroid use, adverse events, serious 
adverse events, and disease-related events. 
 
To clarify requirements for recording and reporting disease-related events. 


Product:  AMG 592 
Protocol Number:  20160283 
Date:  04 December 2018 
Page 1 of 53 
CONFIDENTIAL 
 
 
Amendment 2 
Protocol Title:  A Phase 1b/2 Open-label Study Evaluating the Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics, and Efficacy of AMG 592 in Adult Subjects 
With Steroid Refractory Chronic Graft versus Host Disease 
 
Amgen Protocol Number (AMG 592) 20160283 
EudraCT Number:  2017-000763-33 
NCT Number:  NCT03422627 
 
Amendment Date: 
04 December 2018 
 
Rationale: 
The main purpose of this protocol amendment is to update the Phase 1b study design in 
order to provide more robust data.  In addition this amendment includes edits that clarify 
eligibility criteria and study conduct rules, remove restrictions that decrease subject 
retention, and align the protocol with current Amgen guidelines.  The following changes 
were made: 
Changes to Study Design: 
 
Increased Phase 1b cohort size of future dosing cohorts from n = 3 to up to n = 6 in 
order to provide more robust PK/PD and safety data for each dose level 
 
Clarified that dosing cohorts may be added or removed at any time after completion 
of the first cohorts 
 
Removed optional cohorts 1b/2b as these do not need to be depicted as optional 
cohorts may be added at any time in the study as needed 
 
Added 1a/2a dose expansion cohorts to align with DLRM decision 
 
Made final dose expansion cohort of n = 10 subjects optional 
 
Revised study schema to align with Study Design language  
Clarification of Entry Criteria and Study Conduct Rules: 
 
Clarified that for inclusion criterion 105, lines of therapy consisting of concurrent 
medications or interventions count as 2 separate treatments 
 
Clarified that inclusion criteria 106 and 107 do not require subjects to be taking 
corticosteroids or other immunosuppressants at study entry, but do require those 
subjects who are taking these medications at study entry to be on stable doses 
Approved 
 
 


Product:  AMG 592 
Protocol Number:  20160283 
Date:  04 December 2018 
Page 2 of 53 
CONFIDENTIAL 
 
 
 
Clarified that the intent of the urine toxicology screen is to exclude illicit drugs; 
prescription medications taken under the direction of a physician are not 
exclusionary 
 
Clarified that PFTs are strongly preferred as part of the NIH Form A efficacy 
assessment and are required at the Baseline or Screening visit and in all subsequent 
NIH Form A assessments for those subjects with abnormal PFTs at baseline, known 
pulmonary GVHD or new respiratory symptoms. 
 
Clarified that the 2 (or 6) minute walk test is not required for the NIH Form A 
assessment 
 
 
  Individual subject 
dose reduction is not permitted in the Phase 1b part of the study. 
 
Clarified rules for use of systemic corticosteroids for GVHD flares occurring in the 
first 4 weeks of study participation 
 
Specified that Phase 1b subjects who discontinue study participation before 
receiving fewer than 4 doses (instead of 2) of AMG 592 will be replaced to ensure 
adequate PK and PD information 
 
Added T-SPOT to the list of acceptable assays for TB testing to reflect standard of 
care.  Added criteria for inclusion for subjects with an indeterminate Quantiferon or 
T-SPOT test, given the high prevalence of anergy in this immunosuppressed 
population 
Changes to Improve Subject Retention: 
 
Revised entry criterion 104, definition of moderate to severe steroid refractory 
cGVHD: 
o Remove requirement for diagnosis within the past 2 years 
o Remove requirement to be steroid refractory within the past 12 months 
 
Modified alcohol restrictions after the 4-week DLT evaluation period in eligible 
subjects  
 
Increased visit window duration after the week 16 visit 
 
 as part of the Staging and NIH 
Form A evaluations. 
Changes to Align with Current Amgen Guidelines: 
 
Revised Appendix 3 DLRM and Section 5.1.1 Phase 1b study design to align with 
new Early Development Review Committee Guidelines  
Approved 
 
 


Product:  AMG 592 
Protocol Number:  20160283 
Date:  04 December 2018 
Page 3 of 53 
CONFIDENTIAL 
 
 
Other Miscellaneous Changes: 
 
 
 
Changed subject urine drug/alcohol testing, during screening, from the local 
laboratory to the central laboratory for operational ease 
 
Changed to 1-sided test with a significance level of 0.025, which was a request from 
the IRB of the lead PI site 
Approved 
 
 


Product:  AMG 592 
Protocol Number:  20160283 
Date:  22 August 2017 
Page 1 of 56 
Amendment 1 
Protocol Title:  A Phase 1b/2 Open-label Study Evaluating the Safety, Tolerability, 
pharmacokinetics, Pharmacodynamics, and Efficacy of AMG 592 in Adult Subjects 
with Steroid Refractory Chronic Graft versus Host Disease 
 
Amgen Protocol Number AMG 592 20160283 
 
 
Amendment Date: 
22 August 2017 
Rationale: 
The changes to this protocol include the following: 
• 
Administrative, typographical, abbreviation clarifications and formatting changes 
were made throughout the protocol.  The template was updated to match the 
new Amgen template Version 15.2; 14 April 2017. 
• 
Key Sponsor Contact and supporting information was updated to 
, 
MD. 
• 
The primary objective for the phase 1b portion of the study was updated to clarify 
the intent to use the phase 1 data to determine the maximum tolerated dose and 
support the determination of the 
   
• 
Due to nonclinical safety findings the maximum dose to be administered in the 
study has been changed to 
 µg administered every other week (Q2W).  
Information associated with the steady state exposures and corresponding safety 
exposure margins have been updated to include the 
 µg Q2W dose.  The 
 µg Q2W dose is predicted to achieve similar Treg expansion as seen in 
chronic GVHD (cGVHD) subjects treated with low-dose IL-2 at 12 weeks while 
still maintaining adequate safety margins relative to the no adverse effect level in 
the 3-month toxicology study in cynomolgus monkeys. 
• 
To accommodate the change in formulation, the information regarding product 
packaging has been updated to indicate that AMG 592 is a liquid formulation that 
will be provide in glass vials.  In addition to the abdomen, administration of 
AMG 592 was updated to include the upper arm and thigh as sites for the SC 
injection.  In addition, observation following study drug administration was 
updated to indicate that the subject will remain for at least 1 hour following the 
first and second dose of AMG 592 followed by 30 minutes for all remaining 
doses. 
CONFIDENTIAL 
 
 
Approved 
 
 


Product:  AMG 592 
Protocol Number:  20160283 
Date:  22 August 2017 
Page 2 of 56 
• 
A GVHD Staging procedure was added to the screening visit in the Schedule of 
Activities to clarify the procedures required for determining potential subject 
eligibility to participate in the study.  The inclusion criteria were updated to clarify 
that based on this assessment, subjects had moderate to severe cGVHD present 
at both the screening along with the diagnostic history.  The continued presence 
of symptoms at the baseline visit were also included. 
• 
Information was added to clarify those procedures which are specific for 
phase 1b or 
  Including the reduction in the duration of time where 
immunosuppressive background therapy dose reductions are not permitted from 
16 weeks to 8 weeks. 
• 
Clarifying language was added regarding the eligibility and continued 
participation of subjects with elevations in liver function tests and abnormalities in 
pulmonary function associated with cGVHD.  In addition, the assessment of drug 
induced liver injury (DILI) was clarified to indicate that DILI would be assessed by 
the PI to determine if the abnormality was related to cGVHD or should be 
evaluated as a potential DILI event.  The evaluation of DILI was also clarified to 
indicate that associated testing may be performed by the local laboratory. 
• 
Removed eligibility exception for elevated total bilirubin for subjects with Gilbert’s 
Syndrome. 
• 
Pharmacokinetics will be determined using serum samples rather than plasma 
samples. 
• 
Subgroup analyses were updated to include prior radiation status and 
conditioning regimen (myeloablative versus non-myeloablative). 
• 
The NIH defined diagnostic or distinctive features of cGVHD and the NIH Global 
Severity were updated to match the 2014 criteria. 
• 
For consistency throughout the protocol, the current Common Terminology 
Criteria for Adverse Events (CTCAE) grades are presented without associated 
laboratory values. 
• 
Updates for the timing of assessments in both phase 1b and 
 were 
included to ensure the alignment of the collection of appropriate efficacy and 
safety data. 
• 
The Safety Follow-Up Visit was updated to require in-clinic assessment of the 
subjects rather than a phone call assessment.  Urine pregnancy testing was also 
added for women of childbearing potential to confirm pregnancy status up to 
6 weeks posttreatment. 
CONFIDENTIAL 
 
 
Approved 
 
 

SAP_001.pdf: 
Product: efavaleukin alfa       
 
Protocol Number: 20160283 
Date: 31 January 2023 
Page 1 of 64 
 
CONFIDENTIAL 
 
 
Confidential Clinical Trials 
Statistical Analysis Plan 
Protocol Title: 
A Phase 1b/2 Open-label Study Evaluating the Safety, 
Tolerability, Pharmacokinetics, Pharmacodynamics, 
and Efficacy of efavaleukin alfa in Adult Subjects With 
Steroid Refractory Chronic Graft Versus Host Disease 
Short Protocol Title: 
Safety and Efficacy of efavaleukin alfa in Subjects With 
Steroid Refractory Chronic Graft versus Host Disease 
Protocol Number: 
20160283 
NCT Number: 
NCT03422627 
Authors: 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive,  
Thousand Oaks,  
CA, 91320, USA 
SAP Date: 
Document Version 
Date 
Original 
Amendment 1 (v1.0)  
Amendment 2 (v2.0) 
Amendment 3 (v3.0) 
14 December 2017 
17 August 2020 
12 September 2022 
31 January 2023 


Product: efavaleukin alfa       
 
Protocol Number: 20160283 
Date: 31 January 2023 
Page 2 of 64 
 
CONFIDENTIAL 
 
 
Confidential Clinical Trials 
Version Number 
Date 
 
Summary of Changes,  
including rationale for changes 
Original  
14 December 2017 
NA 
[Amendment 1 (v1.0)] 
17 August 2020 
Changes related to protocol 
amendment 2 (4 December 2018) 
and protocol amendment 3 (26 
August 2019)  
[Amendment 2 (v2.0)] 
12 September 2022 
The statistical analysis plan for this 
study was amended to reflect the 
changes in protocol amendment 4 (8 
December 2020)  and 5 (22 June 
2021), and the changes due to the 
decision to terminate the study early 
without conducting phase 2. Editorial 
changes and minor clarifications 
were also implemented throughout 
the document.  
 
Description of Global Changes 
 
Removed all the text and 
analysis related to Phase 2 
part. 
 
Removed interim analysis 
section for Phase 1b. 
 
Added language on the 
additional extended treatment 
period beyond week 104 in 
Study Design section.  
 
Updated the Study Design 
section and Sample Size 
section to include Cohort 5. 
 
Updated Important Protocol 
Deviations section to include 
summaries for COVID-19 
IPDs. 
 
Events of interest and AEs 
identified by COVID-19 
MedDRA queries are added 
to Adverse events and 
Disease-related Events 
section. 
[Amendment 3 
(v3.0)] 
31 January 2023 
The statistical analysis plan was 
amended to reflect the following 
changes: 
 
Description of Global Changes 


Product: efavaleukin alfa       
 
Protocol Number: 20160283 
Date: 31 January 2023 
Page 3 of 64 
 
CONFIDENTIAL 
 
 
Confidential Clinical Trials 
 
Added the decision made in 
Ad hoc DLRM 
 
Added a few definitions like 
actual treatment period, 
baseline medication, 
planned treatment period, 
dose reduction period, anti-
drug antibody analysis set 
 
Added immunosuppressant 
medication in baseline 
characteristics  
 
Added additional 
summaries for TEAE by 
antibody status, additional 
EOIs and systemic 
corticosteroid dose 
reduction 


Product: efavaleukin alfa       
 
Protocol Number: 20160283 
Date: 31 January 2023 
Page 4 of 64 
 
CONFIDENTIAL 
 
 
Confidential Clinical Trials 
Table of Contents 
Table of Contents ................................................................................................... 4 
1. 
Introduction ........................................................................................................... 11 
2. 
Objectives, Endpoints and Hypotheses ................................................................. 11 
2.1 
Objectives and Endpoints .......................................................................... 11 
2.2 
Hypotheses and/or Estimations ................................................................. 12 
3. 
Study Overview .................................................................................................... 12 
3.1 
Study Design ............................................................................................. 12 
3.2 
Sample Size .............................................................................................. 17 
3.2.1 
Replacement of Subjects ........................................................... 17 
3.2.2 
Number of Sites ......................................................................... 17 
3.3 
Adaptive Design ........................................................................................ 17 
4. 
Covariates and Subgroups ................................................................................... 17 
4.1 
Planned Covariates ................................................................................... 17 
4.2 
Subgroups ................................................................................................. 17 
5. 
Definitions ............................................................................................................. 17 
5.1 
Basic Definitions........................................................................................ 17 
5.2 
Study Dates .............................................................................................. 18 
5.3 
Subject Disposition .................................................................................... 19 
5.4 
Arithmetic Calculations .............................................................................. 21 
5.5 
Definitions ................................................................................................. 22 
5.6 
Demographic and Baseline Characteristics ............................................... 28 
6. 
Analysis Sets ........................................................................................................ 29 
6.1 
Safety Analysis Set ................................................................................... 29 
6.2 
DLT Analysis Set ....................................................................................... 29 
6.3 
Pharmacokinetic/Pharmacodynamic Analyses Set(s) ................................ 29 
6.3.1 
Pharmacokinetic (PK) Concentration Analysis Set..................... 29 
6.3.2 
Pharmacodynamic (PD) Analysis Set ........................................ 29 
6.4 
Anti-drug Antibody Analysis Set ................................................................ 29 
7. 
Planned Analyses ................................................................................................. 29 
7.1 
DLRMs ...................................................................................................... 29 
7.2 
Final Analysis ............................................................................................ 30 
8. 
Data Screening and Acceptance ........................................................................... 30 
8.1 
General Principles ..................................................................................... 30 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 30 
8.3 
Handling of Missing and Incomplete Data ................................................. 30 
8.3.1 
Efficacy ...................................................................................... 31 
8.3.2 
Safety ........................................................................................ 31 


Product: efavaleukin alfa       
 
Protocol Number: 20160283 
Date: 31 January 2023 
Page 5 of 64 
 
CONFIDENTIAL 
 
 
Confidential Clinical Trials 
8.4 
Detection of Bias ....................................................................................... 31 
8.5 
Outliers ..................................................................................................... 31 
8.6 
Distributional Characteristics ..................................................................... 31 
8.7 
Validation of Statistical Analyses ............................................................... 31 
9. 
Statistical Methods of Analysis.............................................................................. 32 
9.1 
General Considerations ............................................................................. 32 
9.2 
Subject Accountability ............................................................................... 32 
9.3 
Important Protocol Deviations ................................................................... 32 
9.4 
Demographic and Baseline Characteristics ............................................... 33 
9.4.1 
Demographic Characteristics ..................................................... 33 
9.4.2 
Baseline Characteristics ............................................................ 33 
9.5 
Efficacy Analyses ...................................................................................... 33 
9.5.1 
Analyses of Primary Efficacy Endpoint(s) .................................. 33 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s).............................. 33 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) ............................. 34 
9.6 
Safety Analyses ........................................................................................ 34 
9.6.1 
Analyses of Primary Safety Endpoint(s) ..................................... 34 
9.6.2 
Adverse Events and Disease-related Events ............................. 34 
9.6.2.1 
Dose Limiting Toxicities ........................................... 35 
9.6.3 
Laboratory Test Results ............................................................ 36 
9.6.3.1 
Chemistry and Hematology ..................................... 36 
9.6.4 
Vital Signs ................................................................................. 37 
9.6.5 
Physical Measurements ............................................................ 37 
9.6.6 
Electrocardiogram ..................................................................... 37 
9.6.7 
Antibody Formation ................................................................... 37 
9.6.8 
Exposure to Investigational Product .......................................... 37 
9.6.9 
Exposure to Concomitant Medication ........................................ 38 
9.7 
Other Analyses ......................................................................................... 38 
9.7.1 
Analyses of Pharmacokinetic or 
Pharmacokinetic/Pharmacodynamic Endpoints ......................... 38 
9.7.1.1 
Analysis of Pharmacokinetic Endpoint ..................... 38 
9.7.1.2 
Analysis of Pharmacodynamic Endpoints ................ 38 
9.7.1.3 
PK/PD Analysis ....................................................... 39 
9.7.2 
Analyses of Clinical Outcome Assessments .............................. 39 
9.7.3 
Analyses of Biomarker Endpoints .............................................. 40 
10. 
Changes From Protocol-specified Analyses.......................................................... 40 
11. 
Literature Citations / References ........................................................................... 41 
12. 
Prioritization of Analyses....................................................................................... 42 


Product: efavaleukin alfa       
 
Protocol Number: 20160283 
Date: 31 January 2023 
Page 6 of 64 
 
CONFIDENTIAL 
 
 
Confidential Clinical Trials 
13. 
Data Not Covered by This Plan............................................................................. 42 
14. 
Appendices ........................................................................................................... 43 
Appendix A.  Technical Detail and Supplemental Information Regarding 
Statistical Procedures and Programs ........................................................ 44 
Appendix B.  Reference Values/Toxicity Grades ................................................... 46 
Appendix C.  Bayesian Logistic Regression Model ............................................... 47 
Appendix D.  Disease Related Events Table ......................................................... 50 
Appendix G.  Analytical Windows ......................................................................... 59 
 


Product: efavaleukin alfa       
 
Protocol Number: 20160283 
Date: 31 January 2023 
Page 7 of 64 
 
CONFIDENTIAL 
 
 
Confidential Clinical Trials 
List of Table 
.................. 47 
Table 2.  Probability Profile of Low, Mild and High Scenario .......................................... 49 
Table 3.  Summarized Simulation Results for BLRM ..................................................... 49 
List of Figures 
Figure 1.  Study Schema ............................................................................................... 15 
 


Product: efavaleukin alfa       
 
Protocol Number: 20160283 
Date: 31 January 2023 
Page 8 of 64 
 
CONFIDENTIAL 
 
 
Confidential Clinical Trials 
List of Abbreviations and Definition of Terms 
 
Abbreviation or Term Definition/Explanation 
AE 
adverse event 
ALT 
alanine transaminase 
ANC 
absolute neutrophil count 
ARDS 
acute respiratory distress syndrome 
AUC 
area under the concentration-time curve 
AUClast 
area under the concentration from time 0 to the time of the last 
quantifiable concentration 
AUCtau 
area under the concentration-time curve over a dosing interval 
BLRM 
bayesian logistic regression model 
BSA 
body surface area 
CD 
cluster of differentiation 
cGVHD 
chronic graft versus host disease 
Cmax 
maximum observed serum concentration 
COVID-19 
coronavirus disease 
CPMS 
clinical pharmacology, modeling and simulation 
CRF 
case report form 
CTCAE 
common terminology criteria for adverse events 
CV 
co-efficient of variation 
DILI 
drug-induced liver injury 
DLRM 
dose level review meeting 
DLT 
dose limiting toxicity 
DMP 
data management plan 
DOR 
duration of response 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
EOT 
EOET 
end of treatment 
end of extended treatment 
EOS  
end of study 
FEV1 
forced expiratory volume in 1 second 


Product: efavaleukin alfa       
 
Protocol Number: 20160283 
Date: 31 January 2023 
Page 9 of 64 
 
CONFIDENTIAL 
 
 
Confidential Clinical Trials 
Abbreviation or Term Definition/Explanation 
Foxp3 
forkhead box P3 
GI 
gastrointestinal 
GSO-DM 
global study operations-data management 
GVHD 
graft versus host disease 
ICH 
international council for harmonisation 
IL-2 
interleukin 2 
Interactive Voice 
Response System 
(IVRS) 
telecommunication technology that is linked to a central 
computer in real time as an interface to collect and process 
information   
Interactive Web 
Response System 
(IWRS) 
web based technology that is linked to a central computer in 
real time as an interface to collect and process information  
IP 
IPD 
investigational product 
important protocol deviations 
KM 
kaplan-meier 
MAD 
multiple ascending dose 
MedDRA 
medical dictionary for regulatory activities 
NI 
no involvement 
NIH 
national Institutes of health  
NK cells 
natural killer cells 
NKT cells 
natural killer T cells 
NRI 
non-responder imputation 
NS 
not significant 
OMRS 
total score for all mucosal changes 
PD 
pharmacodynamics or progressive disease 
PFT 
pulmonary function test 
PI 
principal investigator 
PK 
pharmacokinetic 
PKDM 
pharmacokinetics and drug metabolism 
P-ROMQW 
QW 
Q2W 
patient related outcome measures 
every week 
every 2 weeks 


Product: efavaleukin alfa       
 
Protocol Number: 20160283 
Date: 31 January 2023 
Page 10 of 64 
 
CONFIDENTIAL 
 
 
Confidential Clinical Trials 
Abbreviation or Term Definition/Explanation 
RBC 
red blood cell 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SFU 
safety follow up 
SOC 
standard of care 
Tcon 
conventional T cells 
Tmax 
time of maximum observed concentration 
TPI 
toxicity probability interval 
Teff 
T effector cells 
Treg 
regulatory T cells 
ULN 
USA 
upper limit of normal 
united states of america 


Product: efavaleukin alfa       
 
Protocol Number: 20160283 
Date: 31 January 2023 
Page 11 of 64 
 
CONFIDENTIAL 
 
 
Confidential Clinical Trials 
1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol for study 20160283, efavaleukin 
alfa dated 22 June 2021. The scope of this plan includes the analysis that is planned for 
phase 1b part and will be executed by the Global Biostatistical Sciences (GBS) 
department unless otherwise specified. Analyses described in the protocol for the phase 
2 part will not be conducted as the study is being terminated early. 
2. 
Objectives, Endpoints and Hypotheses 
2.1 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
To evaluate the safety and tolerability 
of multiple ascending doses of 
efavaleukin alfa in subjects with 
steroid refractory chronic graft versus 
host disease (cGVHD)  
 Incidence of dose limiting toxicities 
(DLTs) at first 4 weeks 
 Incidence of all treatment-related and 
treatment-emergent adverse events 
and serious adverse events 
Secondary 
Exploratory 


Product: efavaleukin alfa       
 
Protocol Number: 20160283 
Date: 31 January 2023 
Page 12 of 64 
 
CONFIDENTIAL 
 
 
Confidential Clinical Trials 
Objectives 
Endpoints 
2.2 
Hypotheses and/or Estimations 
Clinical hypothesis: efavaleukin alfa will be safe and well-tolerated in subjects with 
steroid refractory cGVHD. 
There is no statistical hypothesis planned for the phase 1b part of the study. 
3. 
Study Overview 
3.1 
Study Design 
This is an open-label, multi-center phase 1b/2 study to evaluate the safety and efficacy 
of efavaleukin alfa in subjects with steroid refractory cGVHD.   
The phase 1b part of the study will be conducted as a multiple ascending dose (MAD) 
study. Each dosing cohort will consist of between 3 and 6 DLT-evaluable subjects who 
will receive efavaleukin alfa SC either every week (QW) or every 2 weeks (Q2W) plus 
protocol permitted background therapy for 52 weeks. The DLT evaluation period is 
defined as 4 weeks after the first dose of study IP. At the discretion of the Sponsor, 
following discussion and agreement between the principal investigator and medical 
monitor, subjects responding to efavaleukin alfa (as assessed by the end of week 50), 
who wish to continue treatment, may continue to receive efavaleukin alfa treatment at 
their current dosing regimen for up to an additional 52 weeks. The remaining subjects 
will complete the week 52/EOT visit. All subjects who continue to receive efavaleukin 
alfa during the extended dosing period will be re-evaluated at week 76 for their response 
to treatment. Following discussion and agreement between the principal investigator and 
medical monitor, the Sponsor may decide to allow these subjects to continue treatment 


Product: efavaleukin alfa       
 
Protocol Number: 20160283 
Date: 31 January 2023 
Page 13 of 64 
 
CONFIDENTIAL 
 
 
Confidential Clinical Trials 
through week 102 (Q2W dose) or week 103 (QW dose). Subjects participating in 
extended dosing will complete the week 104/end of extended treatment (EOET) visit. At 
the discretion of the Sponsor, following discussion and agreement between the principal 
investigator and medical monitor, subjects responding to efavaleukin alfa (as assessed 
by the end of week 104), who wish to continue treatment beyond week 104, may 
continue to receive efavaleukin alfa treatment at their current dosing regimen for up to 
an additional 156 weeks. Only subjects who are deemed eligible to continue extended 
dosing beyond week 102 or week 103 will complete dosing at week 104. The remaining 
subjects will complete the week 104/EOET visit. All subjects who continue to receive 
efavaleukin alfa during the extended dosing period will be re-evaluated every 6 months 
for their response to treatment. Following discussion and agreement between the 
principal investigator and medical monitor, the Sponsor may decide to allow these 
subjects to continue treatment through week 258 (Q2W dose) or week 259 (QW dose). 
Subjects participating in extended dosing through week 258 or 259 will complete the 
week 260/EOET visit. All subjects will complete the 6-week safety follow-up after the last 
dose of efavaleukin alfa. 
Five dose levels are planned:  
 g every 2 weeks (Q2W) (cohorts 1a), 
 g every 
week (QW) (cohorts 2a), 
 g Q2W (cohort 3), 
 g QW (cohort 4), and 
 g 
Q2W (cohort 5).  Dose levels 1a (
 g Q2W) and 2a (
 g QW) will be enrolled 
concurrently. Three subjects each will be assigned to cohorts 1a (
 g Q2W) and 2a 
(
 g QW) alternately (total of 6 subjects). After the last subject completes the DLT 
evaluation period, a dose level review meeting (DLRM) will occur and if deemed 
necessary, 3 additional subjects each will be assigned to cohorts 1a and 2a alternately 
(total of 6 subjects) to gain additional information. After the last subject completes the 
DLT evaluation period, a DLRM will occur and if dose escalation is deemed appropriate, 
subjects will be enrolled in cohorts 3 (
 g Q2W) 4 (
 g QW), and 5 (
 g 
Q2W) as follows: first, 3 subjects will be enrolled in cohorts 3. An internal safety review 
will be conducted by the Amgen Medical Monitor and Global Safety Officer after the first 
3 subjects complete the DLT evaluation period. If concerning safety issues are identified, 
a DLRM will occur to assess if it is safe to proceed with additional enrollment in cohort 3 
and concurrent enrollment in cohort 4. If no concerning safety issues are identified in 
these first 3 subjects, enrollment of the remaining 3 subjects in cohort 3 will proceed 
without a DLRM. Concurrently, enrollment of 6 subjects in cohort 4 will begin with 
alternate assignment of subjects between cohorts 3 and 4 until enrollment of cohort 3 


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has completed. Enrollment of 6 subjects in cohort 5 will begin after the DLRM for cohort 
4 is complete. DLRMs for cohorts 3, 4 and 5 will occur after the last subject in that cohort 
completes the DLT evaluation period.  
All planned dose levels for a given cohort may be adjusted at any time based on 
emerging data. Additional dosing cohorts may be added, removed or substituted at any 
time based on emerging data and the results of continuous modeling. As a result of a 
recommendation from an ad hoc DLRM, Amgen discontinued enrollment to cohort 
5 at the planned 
 mcg Q2W dose. Subjects who were on-going at the time of 
this decision had their dose reduced to 
 g Q2W for their remaining visits.   
After there is at least 1 DLT observed at any dose level, a Bayesian logistic regression 
model (BLRM) (Bailey et al, 2009; Neuenschwander et al, 2008) will be used to inform 
dose escalation and the results of this analysis will be provided to the DLRM. Three 
toxicity probability intervals (TPI) of DLT will be defined: target TPI (20 to 30), 
excessive TPI (30 to 60) and unacceptable TPI (60 to 100). Adverse events 
meeting DLT criteria after week 4 and PD information may also be included in the model, 
as available. The model will recommend an MTD as the dose with highest probability in 
the target TPI, but with less than 25 probability in excessive TPI and unacceptable TPI.  
Lower dose levels, intermediate dose levels or alternative dosing schedules may be 
considered based on all available information as long as they do not exceed the 
estimated MTD per the model. In addition, Amgen may add subjects to dose levels 
below the MTD in order to better characterize PK and PD. After DLT is observed, the 
BLRM model will be run after each dosing cohort and may be run at any time to 
continuously update the MTD information. For technical details of BLRM, please refer to 
Appendix C. 
The study has been terminated early and therefore, the optional dose expansion cohort 
of phase 1b and the phase 2 part of the study is canceled.  
The overall study design is described by a study schema in Figure 1. The endpoints are 
defined in Section 2.1. 


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Figure 1.  Study Schema  
Cohort 1a:  
µg Q2W (N = 3):  52 weeksc
SFU/EOS:  6 weeks
DLRM
Cohort X, Y…:  xx, y y, µga
Additional Dosing Cohorts may  be added 
or remov ed af ter completion of  
Cohorts 1a/2ab:  52 weeksc
SFU/EOS
6 weeks
DLRM
Optional dose expansion cohort:  up to N = 10:  52 weeksc
SFU/EOS:  6 weeks
Cohort 2a:  
µg QW (N = 3):  52 weeksc
SFU/EOS:  6 weeks
Cohort 1a expansion:  
µg Q2W (N = 3):  52 weeksc
SFU/EOS:  6 weeks
DLRM
Cohort 2a expansion: 
µg QW (N = 3):  52 weeksc
SFU/EOS:  6 weeks
Cohort 3:  
µg Q2W (N = 3):  52 weeksc
SFU/EOS:  6 weeks
Cohort 3:  
µg Q2W (N = 3):  52 weeksc
SFU/EOS:  6 weeks
Cohort 4:  
µg QW (N = 6):  52 weeksc
SFU/EOS:  6 weeks
DLRM (if applicable)
DLRM
DLRM
Cohort 5:  
µg Q2W (N = 6):  52 weeksc
SFU/EOS:  6 weeks
DLRM
 
DLRM  dose level review meeting; EOET  end of extended treatment; PD  pharmacodynamics; PK  pharmacokinetics; TPI  toxicity 
probability interval; SFU  safety follow-up; EOS  end of study; Q2W  every 2 weeks; QW  every week  
a Doses for subsequent cohorts will be determined by results of Bayesian TPI and PK/PD modeling of previous cohorts. 
b A DLRM is required for escalation to higher doses but not for allocation of additional subjects to doses equivalent to or lower than 
previously given that have been deemed tolerable. 
c At the discretion of the Sponsor, following discussion and agreement between the principal investigator and medical monitor, subjects 
responding to efavaleukin alfa (as assessed by the end of week 50), who wish to continue treatment, may continue to receive 
efavaleukin alfa treatment at their current dosing regimen for up to an additional 52 weeks. The remaining subjects will complete the 
week 52/EOT visit. All subjects who continue to receive efavaleukin alfa during the extended dosing period will be reevaluated at week 


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76 for their response to treatment. Following discussion and agreement between the principal investigator and medical monitor, the 
Sponsor may decide to allow these subjects to continue treatment through week 102 (Q2W dose) or week 103 (QW dose). Subjects 
participating in extended dosing through week 104 will complete the week 104/EOET visit. At the discretion of the Sponsor, following 
discussion and agreement between the principal investigator and medical monitor, subjects responding to efavaleukin alfa (as assessed 
by the end of week 104), who wish to continue treatment beyond week 104, may continue to receive efavaleukin alfa treatment at their 
current dosing regimen for up to an additional 156 weeks. Only subjects who are deemed eligible to continue extended dosing beyond 
week 102 or week 103 will complete dosing at week 104. The remaining subjects will complete the week 104/EOET visit. All subjects 
who continue to receive efavaleukin alfa during the extended dosing period will be reevaluated every 6 months for their response to 
treatment. Following discussion and agreement between the principal investigator and medical monitor, the Sponsor may decide to allow 
these subjects to continue treatment through week 258 (Q2W dose) or week 259 (QW dose). Subjects participating in extended dosing 
through week 258 or 259 will complete the week 260/EOET visit. All subjects will complete the 6-week safety follow-up after the last dose 
of efavaleukin alfa. 
 


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3.2 
Sample Size 
Approximately 40 subjects will be enrolled in phase 1b of the study, with about 30 
subjects in the dose escalation cohorts and approximately 10 subjects in the optional 
dose expansion cohort. The total sample size may be higher than 40 subjects if, 
following a DLRM recommendation or Amgen decision to evaluate additional doses, 
dosing cohorts are added and/or existing cohorts are expanded; or subjects are 
replaced. Additional subjects may be enrolled in each cohort to enable all screened 
eligible subjects to participate in the study.  
With 40 subjects receiving efavaleukin alfa, there is an 87 chance of detecting an 
adverse event with a true incidence rate of 5. Without the optional dose expansion 
cohort (ie, with 30 subjects), the chance of detecting an adverse event with a true 
incidence rate of 5 reduces to 79. 
3.2.1 
Replacement of Subjects 
Subjects may be replaced if they receive fewer than 4 doses of efavaleukin alfa prior to 
discontinuing study participation.   
3.2.2 
Number of Sites 
Approximately 14 sites in North America, Europe, and Asia will participate in the study. 
Sites that do not enroll subjects within approximately 3 months of site initiation may be 
closed. 
3.3 
Adaptive Design 
The adaptive design elements implemented for this study is Bayesian logistic regression 
model to assist dose escalation.  
4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
No covariates will be used for this study. 
4.2 
Subgroups 
No subgroup analyses will be conducted for this study. 
5. 
Definitions 
5.1 
Basic Definitions 
Investigational Product (IP) 
The term ‘investigational product’ is used in reference to efavaleukin alfa. 
Actual Treatment Received 


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Actual treatment received is the IP the subject actually received regardless of the 
dose specified in the protocol for the cohort.  In cases where a subject received 
multiple different efavaleukin alfa doses, the actual treatment received will be 
based on the highest efavaleukin alfa dose received. 
Study Points of Reference 
Baseline  
For any variable, baseline is the last assessment taken prior to or on the first 
investigational product administration unless stated otherwise; for subjects who did not 
receive any investigational product, baseline is the last assessment on or before the 
enrollment date. 
Study Day 1 
Study day 1 is defined as the first day of administration of the investigational product or 
the day of enrollment if the subject does not receive any investigational product. The day 
prior to Study Day 1 is considered as Day – 1. 
Study Day 
Study day is defined as the number of days from Study Day 1. 
Post study day 1: study day (date of interest – date of Study Day 1)  1 
Pre study day 1: study day (date of interest – date of Study Day 1) 
5.2 
Study Dates 
Informed Consent Date  
The date on which the subject signs the informed consent form. 
Last Dose Date  
The date on which a subject is administered the last dose of IP. 
Subject Level End-of-Study (EOS) Date 
End of study for each subject is defined as the date the subject last completed a 
protocol-specified procedure. The date will be recorded on the End of Study eCRF. 
Progressive Disease Visit 
Progressive disease visit should be performed any time during the study if the 
investigator suspects progressive disease and subject is experiencing worsening of 
cGVHD that requires the addition of new immunosuppressive medication(s) or an 
increase in systemic corticosteroid dose above baseline after week 4 of the study.  


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End of Treatment Visit 
Subjects discontinuing treatment prior to week 52 for any reason (see Section 8.1 in 
protocol) will be asked to complete an End of Treatment visit within a window of  7 days 
of the next regularly scheduled visit after the last dose of efavaleukin alfa, consisting of 
all assessments included in the Week 52 visit.  If the End of Treatment visit for a subject 
occurs  7 days after a progressive disease visit, then the procedures completed at the 
End of Treatment visit should only be those NOT performed at the progressive disease 
visit.  
Subjects participating in the extended dosing, subjects discontinuing treatment prior to 
week 102 (Q2W dosing) or week 103 (QW dosing) will be asked to complete an End of 
Extended Treatment visit within a window of  7 days of the next regularly scheduled 
visit after the last dose of efavaleukin alfa, consisting of all assessments included in the 
Week 104 visit. 
Subjects participating in the extended dosing, subjects discontinuing treatment after 
week 104 but prior to week 258 (Q2W dosing) or week 259 (QW dosing) will be asked to 
complete an End of Extended Treatment visit within a window of  7 days of the next 
regularly scheduled visit after the last dose of efavaleukin alfa, consisting of all 
assessments included in the Week 260 visit. 
Safety Follow-up/End of Study Visit 
Upon completion of the treatment period or permanent discontinuation from the study 
treatment for any reason, a safety follow-up visit will be performed approximately 
6 weeks ( 3 days) after the last dose of efavaleukin alfa. Women of childbearing 
potential will be required to complete a pregnancy test at this visit. 
Study Visit 
Since the actual visit for a subject may not exactly coincide with their scheduled visit 
date, the actual visit date is mapped to the analysis visit as per the analysis visit 
windows described in Appendix G. 
5.3 
Subject Disposition 
Exposed to IP  
Subjects are defined as exposed if they receive at least 1 dose of IP. 
Opted for extended dosing period  


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Subjects are defined as opted for extended dosing period if subject has marked Yes for 
extended dosing on “Extended Dosing Schedule” eCRF. 
Enrolled  
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria and has been enrolled via the Interactive Voice Response 
System/Interactive Web Response System (IVRS/IWRS). See protocol Section 6.4 for 
further details. The subject will be marked as enrolled on Enrollment eCRF and 
enrollment date will be included. 
On-Study  
Subjects are considered on-study when they have enrolled but have not ended the 
study. 
Planned Treatment Period 
The time period from study day 1 until end of study or, for cohort 5 subjects, until 
the day before the first dose of IP at the reduced dose (
 mcg), whichever 
occurred first. 
Dose Reduction Period 
For cohort 5 subjects, the time period from the first dose of IP at the reduced dose 
(
 mcg) until end of study, if applicable.  
Completed IP  
Subjects are defined as completing IP if the reason for ending IP on End of IP 
administration eCRF is marked as Completed. Based on whether subjects opted for 
extended dosing, these subjects will be stratified for summary purposes into those who 
1) completed IP up to week 52 and did not opt for extended dosing, and 2) completed IP 
through extended dosing period.  
Completed Study  
Subjects are defined as completing study if the reason for ending the study on EOS 
eCRF is marked as Completed. Based on whether subjects opted for extended dosing, 
these subjects will be further stratified for summary purposes into those who 1) 
completed the study up to week 52 and did not opt for extended dosing, and 2) 
completed the study through extended dosing period. 


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5.4 
Arithmetic Calculations 
Change from baseline 
Change from baseline is the arithmetic difference between post-baseline and baseline. 
i.e. post-baseline minus baseline. 
Percent change from baseline 
Percent change from baseline is the change from baseline divided by the baseline value 
times 100. If the change from baseline is not equal to 0 and the baseline value is 0 then 
percent change is not defined. If the change from baseline is equal to 0 and the baseline 
value is also 0 then percent change is 0. 
Fold change from baseline 
Fold change from Baseline equals the post-Baseline value divided by the Baseline 
value. If the change from baseline is not equal to 0 and the baseline value is 0 then fold 
change is not defined. If the change from baseline is equal to 0 and the baseline value is 
also 0 then fold change is 1. 
Dose Administered 
The dose administered (g) will be calculated as follows using quantity administered 
(mL), amount of IP used in preparation (mL) and total volume of preparation (mL) as 
reported in the clinical database and packaged drug concentration (mg/mL) as reported 
in manufacturing lot file: 
 
If dilution required,  
 
 
 
Dose Administered  Quantity administered x packaged drug 
concentration x (amount of IP used / total volume of preparation) x 1000; 
 
If dilution not required,  
 
 
Dose Administered  Quantity administered x packaged drug 
concentration x 1000  
If the dilution of IP is not required, the amount of IP used in the preparation of the dose 
and the total volume of preparation are not included in the calculation. 
Number of days on IP 
Number of days on IP is defined as last dose date – first dose date  1 


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Estimated glomerular filtration rate (eGFR) 
Estimated glomerular filtration rate at any visit will be calculated as follows using serum 
creatinine (umol/L) collected as part of chemistry labs at that visit and demographic 
information collected at screening: 
For Japanese subjects:  
eGFR (mL/min/1.73 m²)  194 x [(Creatinine/88.4)-1.094] * (Age-0.287) * 0.739 (if female) 
For non-Japanese subjects:  
eGFR (mL/min/1.73 m²)  175 x [(Creatinine/88.4)-1.154] * (Age-0.203) * 1.212 (if black) * 
0.742 (if female) 
5.5 
Definitions  
AUClast  
Area under the concentration-time curve from time 0 (time of investigational product 
administration) to the time of the last quantifiable concentration. 
AUCtau 
Area under the concentration-time curve after the first and last doses. 
Cmax 
Maximum observed serum concentration. 
Dose Limiting Toxicity (DLT)  
The DLT evaluation period for each subject is 4 weeks from the first dose of efavaleukin 
alfa. To be evaluable for a DLT, subjects must have received at least 2 doses of 
efavaleukin alfa, or have experienced a DLT within the DLT evaluation period.  All 
subjects who experience a DLT will discontinue study therapy and complete safety 
follow up. Dose limiting toxicity events will be used to guide dose escalation decisions 
and to determine the maximum tolerated dose as described in Section 3.1. 
These events will be marked as DLT on Events eCRF. 
The following DLT criteria apply to the study: 


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 
Non-hematological toxicity  grade 4 related to efavaleukin alfa.  Non-hematological 
laboratory abnormalities without clinical significance will not be considered DLTs 
(based upon the investigator’s discretion in conjunction with Amgen). 
 
Hematological toxicity  grade 4 related to efavaleukin alfa defined as decrease in 
peripheral counts (ANC or platelets) persisting longer than 72 hours, as measured by 
2 separate results, that are not related to malignant disease relapse, infection, or 
other etiologies. 
 
Constitutional events (i.e., fever, fatigue)  grade 3 that are classified as serious 
adverse events by the investigator and related to efavaleukin alfa. 
 
Infection: Infection is considered an expected complication of cGVHD and its 
treatment. cGVHD itself increases the risk of infection, including life threatening 
infection. Therefore only grade 4 or 5 infections considered by the investigator to be 
related to efavaleukin alfa will be reviewed by the DLRM to determine whether the 
infection is considered a DLT. 
Subjects who develop an uncontrolled grade 4 life threatening infection (e.g., sepsis, 
ARDS), as assessed by the investigator, will discontinue efavaleukin alfa and remain in 
the study for safety follow-up (see Section 5.4) after completing the 4-week DLT 
evaluation period, subjects will be evaluated by standard safety reporting. 
2014 cGVHD NIH response Consensus criteria algorithm (NIH Form A - 2014) 
All subjects in the study will have their clinical response assessed using the NIH cGVHD 
Response assessment (NIH Form A) as per the 2014 cGVHD NIH Consensus Criteria. 
Subjects will undergo repeat detailed assessment of ocular, oral, cutaneous, 
musculoskeletal, gastrointestinal, hepatic, and pulmonary systems per 
 
 
 


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Treatment Emergent AE (TEAE) 
A treatment emergent adverse event is any adverse event categorized as adverse 
events starting on or after first dose of investigational product as determined by "Did 
event start before first dose of investigational product" equal to "No" or missing on the 
Events eCRF and up to and including 42 days after the last dose of investigational 
product excluding events reported after End of Study date on eCRF form, whichever is 
earlier.  
Treatment-related Treatment Emergent Adverse Event (TRAE) 
A treatment-related AE is any TEAE with the relationship flag on the Adverse Events eCRF 
indicating there is a reasonable possibility that the event may have been caused by 
investigational medicinal product. This assessment is performed by the study investigator. 
In the unlikely event that the relationship flag is missing and an event is TEAE, then it will 
be considered treatment-related and corresponding footnote will be included in the 
summary table. 
Baseline medications 
Baseline medication is defined as any medication with a start date on or before 
Study Day 1 and ongoing while on study.  
Prior and Concomitant medications 
Prior medication is defined as any medication with start date and end date prior to the 
first dose date of IP. Concomitant medication is defined as any medication with start 
date prior to the first dose date of IP but which continued to be taken after the first dose 
of IP or any medication with start date on or after the first dose date of IP and up to and 
including 42 days after the last dose date of IP. 
Duration of Treatment-emergent Injection Site Reaction (ISR) 
Duration  (min (ISR end date, EOS date) – ISR start date)  1. 
5.6 
Demographic and Baseline Characteristics 
Age  
Age in years at the screening visit, which is collected in the eCRF. 
Duration of cGVHD 
Number of years from date of diagnosis of cGVHD (collected in chronic GVHD medical 
history eCRF) to the date of Study Day 1.  


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Duration of steroid refractory cGVHD 
Number of years from date of diagnosis of steroid refractory cGVHD (collected in chronic 
GVHD medical history eCRF) to the date of Study Day 1.  
6. 
Analysis Sets 
6.1 
Safety Analysis Set 
The safety analysis set is defined as all subjects who have received at least 1 dose of 
efavaleukin alfa in the study. All analyses will be conducted on the safety analysis set 
unless noted otherwise.  
6.2 
DLT Analysis Set 
The analysis of DLT will be restricted to DLT analysis set which consists of 
DLT-evaluable subjects in the study. The DLT evaluation period for each subject is 
4 weeks from the first dose of efavaleukin alfa. To be evaluable for a DLT, subjects must 
have received at least 2 doses of efavaleukin alfa, or have experienced a DLT within the 
DLT evaluation period. 
6.3 
Pharmacokinetic/Pharmacodynamic Analyses Set(s) 
6.3.1 
Pharmacokinetic (PK) Concentration Analysis Set   
The PK concentration analysis set consists of all subjects who have received at least 
one dose of efavaleukin alfa and have at least one quantifiable PK sample collected. 
6.3.2 
Pharmacodynamic (PD) Analysis Set   
The PD analysis set consists of all subjects who have received at least one dose of 
investigational product and for whom at least one PD parameters have quantifiable 
baseline sample and at least one quantifiable post-baseline PD sample collected. 
6.4 
Anti-drug Antibody Analysis Set 
The Anti-drug Antibody Analysis Set is defined as the subset of subjects in the 
Safety Analysis Set who had at least 1 evaluable anti-drug antibody test. 
Immunogenicity data will be analyzed according to the actual treatment received. 
7. 
Planned Analyses 
7.1 
DLRMs 
DLRMs: The study will have DLRMs for each cohort after the last subject in the cohort 
completes the DLT evaluation period. Section 3.1 details the timing and scope of each 
DLRM planned for the study. All available data for subjects up to and including the data 
snapshot date will be included in the analysis based on an “as-is” snapshot of the 
database without data locking. Data will be subject to ongoing checks for integrity, 


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completeness and accuracy in accordance with the Data Management Plan; however, 
there is no requirement to resolve outstanding data issues ahead of the DLRM snapshot. 
DLRM analysis will include subject-level listings and plots of available safety data (labs, 
and vitals) for each cohort and the BLRM analysis if required. The recommendations for 
dose escalation/dose modifications will be based on the DLRMs. 
7.2 
Final Analysis 
A final analysis will be performed after the end of the study, i.e., after the last subject in 
phase 1b part of the study completes the study (including the treatment period and 
safety follow-up period), or early terminates. All analyses described in Section 9 will be 
performed at this time. Analyses will be based on all available data. 
Data will be subject to ongoing checks for integrity, completeness and accuracy in 
accordance with the Data Management Plan with the expectation that all outstanding 
data issues are resolved ahead of the final lock.   
8. 
Data Screening and Acceptance 
8.1 
General Principles 
The objective of the data screening is to assess the quantity, quality, and statistical 
characteristics of the data relative to the requirements of the planned analyses. 
8.2 
Data Handling and Electronic Transfer of Data 
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data to be used in the planned analyses. The database will be subject to edit 
checks outlined in the Data Management Plan (DMP). See details of this section in the 
DMP. 
8.3 
Handling of Missing and Incomplete Data 
Subjects may be missing specific data points for a variety of causes. In general, data 
may be missing due to a subject’s early withdrawal from study, a missed visit, or inability 
to evaluate an endpoint at a particular point in time. The general procedures outlined 
below describe what will be done when a data point is missing. 


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8.3.1 
Efficacy 
No data imputation will be performed for missing efficacy endpoints. 
8.3.2 
Safety 
The following imputation for missing or incomplete data will be performed if required: 
Incomplete or missing start/stop dates for adverse event and concomitant medication will 
be imputed as described in Appendix A. 
Laboratory measurements that are below the lower quantification limits will be 
considered equal to the lower limit of quantification for all analyses unless explicitly 
noted otherwise. PD data that are below the lower limit of quantification will be 
considered equal to half of the lower limit of quantification for all analyses unless 
specified otherwise. PD data that are above the upper quantification limits will be 
considered equal to the upper limit of quantification for all analyses unless specified 
otherwise. 
8.4 
Detection of Bias 
Lack of protocol compliance and the potential for biased statistical analyses will be 
examined by assessing the incidence of important protocol deviations in each cohort. 
The clinical study team will identify and document the criteria for important protocol 
deviations. 
8.5 
Outliers 
Outlier data will not be excluded unless scientifically justified.  
PK serum concentration data will be evaluated for outliers by visual inspection and 
decisions to re-assay individual samples will be made in accordance with standard PKDM 
practices.  
8.6 
Distributional Characteristics 
Not Applicable 
8.7 
Validation of Statistical Analyses 
Programs will be developed, maintained, and output will be verified in accordance with 
current risk-based quality control procedures.  
Tables, figures and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.  
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software, for example the SAS System.  


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9. 
Statistical Methods of Analysis 
9.1 
General Considerations 
Standard descriptive statistics will be provided. All binary endpoints will be summarized 
using the number and percentage of subjects. All continuous endpoints will be 
summarized using descriptive statistics including mean, standard deviation, minimum, 
maximum, and number of non-missing observations (n). Summaries will be provided at 
all scheduled time-points unless specified otherwise. Data collected at unscheduled 
visits or time-points will be included in the analysis unless stated otherwise. All safety 
and efficacy analyses will be performed using the Safety Analysis Set based on 
subject’s actual treatment received. 
Only critical subject-level data listings will be provided in the clinical study report.   
9.2 
Subject Accountability 
The number and percent of subjects who are screened, enrolled, have received at least 
one dose of efavaleukin alfa, completed investigational product, discontinued from 
investigational product (including reasons for discontinuing), completed study, 
discontinued the study (including reasons for discontinuing) will be summarized overall 
and by treatment group. Separate subject disposition will be provided for the follow-up till 
week 52 and the extended follow-up.  
Key study dates for the first subject enrolled, last subject enrolled, and last subject’s end 
of study will be presented. 
9.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s initial visit and updated during the IPD reviews throughout the study 
prior to database lock. If a snapshot is taken during the study rather than a database 
lock at the end of the study, categories should be updated during the IPD reviews 
throughout the study prior to database lock. These definitions of IPD categories, 
sub-category codes and descriptions will be used during the course of the study. The 
final IPD list is used to produce the summary of IPD table and the list of subjects with 
IPDs. The number of subjects with important protocol deviations and protocol deviations 
due to COVID-19 will be summarized in a table. A list of protocol deviations for subjects 
impacted by COVID 19 will also be provided. 
Eligibility deviations are defined in the protocol. A list of deviations from eligibility criteria 
will also be generated. 


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9.4 
Demographic and Baseline Characteristics 
Subject demographic and baseline disease characteristics will be summarized and 
include the following variables: 
9.4.1 
Demographic Characteristics  
 
Age (years) at screening (continuous summary statistics) 
 
Age categories (number and percent of subjects in 18 - 64, 65 - 74 years, 
 75 years) 
 
Sex (number and percentage of males and females) 
 
Ethnicity (number and percentage of Hispanic or Latino and Not Hispanic or 
Latino) 
 
Race (number and percentage of subjects in each race, or mixed race 
combination) 
9.4.2 
Baseline Characteristics 
Physical Measurements 
 
Height and weight (continuous summary statistics) 
Disease characteristics: 
 
Duration of cGVHD (continuous summary statistics) 
 
Duration of steroid refractory cGVHD (continuous summary statistics) 
 
Information collected on cGVHD medical history eCRF (e.g. underlying 
malignancy type for which subject received HSCT, Donor type, Stem cell source 
etc.) (number and percentage of subjects) 
 
NIH- Form A-2014 assessment of each organ system (number and percentage of 
subjects) 
 
Overall cGVHD severity as marked on Chronic Graft versus Host Disease 
Staging Evaluation eCRF (number and percentage of subjects) 
  
Baseline immunosuppressant medication 
 
Systemic Corticosteroids  
 
mTOR inhibitors  
 
Calcineurin inhibitors 
9.5 
Efficacy Analyses 
9.5.1 
Analyses of Primary Efficacy Endpoint(s) 
No primary endpoint is an efficacy endpoint. 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s) 
No secondary endpoint is an efficacy endpoint.  


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9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) 
9.6 
Safety Analyses 
9.6.1 
Analyses of Primary Safety Endpoint(s) 
The primary endpoint is safety. The analysis will include the descriptive summary 
statistics for adverse events, disease-related events, laboratory test results, vital signs, 
and physical measurements. Details are described in respective section below.   
9.6.2 
Adverse Events and Disease-related Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 25.0 or later will be 
used to code all adverse events to a system organ class and a preferred term.  
The subject incidence of adverse events will be summarized for all treatment-emergent, 
serious treatment emergent, treatment-related, those leading to withdrawal of 
investigational product, fatal and of special interest (if applicable). The identification of 
adverse events of special interest is a continuous process. Events may be identified and 
documented as the safety profile of the drug. The severity of each adverse event will be 
graded using CTCAE version 4.03 criteria. 
Subject incidence of all treatment-emergent, serious treatment emergent, 
treatment-related, serious treatment-related, those leading to withdrawal of 
investigational product or other protocol-required therapies, and fatal adverse events will 
be tabulated by system organ class and preferred term in descending order of 
frequency. Treatment emergent, serious, and treatment-related events will also be 
presented by preferred term and worst severity grade using CTCAE version 4.03 criteria. 
Overall summary of subject incidence of treatment-emergent adverse events and 


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by preferred term and worst severity grade will be provided by anti-AMG592 and 
 status. Subject incidence of events of interest (standardized 
MedDRA queries and/or Amgen Medical Queries) will also be summarized according to 
their categories, preferred term, and worst severity grade. Events of interest could 
include but are not limited to Hypersensitivity, Tachyarrhythmias, Tachypnea, 
Hematopoietic Cytopenia, Eosinophilic Disorder, Leucocyte Changes, Infection and 
Infestation, Cytokine Release Syndrome, Drug Related Hepatic Disorder, and Injection 
Site Reaction. Number of episodes and duration of treatment-emergent injection site 
reactions will be further summarized.  
Subject incidence of treatment-emergent adverse events identified by COVID-19 
standardized MedDRA queries and serious adverse events occurring on or after the 
COVID-19 infection will also be summarized. 
Subject incidence of disease related events and fatal disease-related events will be 
tabulated by system organ class and preferred term. They are defined for this study in 
Appendix D. 
9.6.2.1 
Dose Limiting Toxicities 
The analysis of the probability of DLT will be based on the Dose Escalation part of the 
study defined in Section 3.1. A listing and summary of the subject incidence of DLT will 
be provided should they occur. After there is at least 1 DLT observed at any dose level, 
a Bayesian logistic regression model (BLRM) (Bailey et al, 2009; Neuenschwander et al, 
2008) will be used to inform dose escalation and the results of this analysis will be 
provided to the each DLRM. Three toxicity probability intervals (TPI) of DLT will be 
defined: target TPI (20 to 30), excessive TPI (30 to 60) and unacceptable TPI 
(60 to 100). Adverse events meeting DLT criteria after week 4 and PD information 
may also be included in the model, as available. The model will recommend an MTD as 
the dose with highest probability in the target TPI, but with less than 25 probability in 
excessive TPI or unacceptable TPI. Lower dose levels, intermediate dose levels, or 
alternative dosing schedules may be considered based on all available information as 
long as they do not exceed the estimated MTD per the model.  
Let 𝒅(𝑑1 , … , 𝑑𝑘 ) denote the vector of all efavaleukin alfa doses to be studied in the 
study. The probability of a DLT at dose level  𝑑𝑖, 𝑖1, … , 𝑘 is assumed to follow a Bernoulli 
distribution with probability 𝑝𝑖 where the logit of  𝑝𝑖  increases linearly with the log of the 
standardized dose in the following 2-parameter logistic model: 


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log [
𝑝𝑖
1 −𝑝𝑖
] 𝑙𝑜𝑔𝑖𝑡(𝑝𝑖)log[𝑎] exp(log[𝑏]) log (
𝑑𝑖
max (𝒅)) 
where a and b are random variables and 𝑑𝑖 is dose level represented by predicted 
 𝑑𝑘 is an additional 
dose assuming Treg concentration  
 that’s higher than the currently planned doses. 
Thus 𝒅
. If additional dose cohorts were added during study 
conduct (e.g., decision following a DLRM), the value of 𝒅 will be updated.  
The probability of each TPI and of a DLT will be summarized by dose along with the 
estimated dose-toxicity curve. A final estimate of the MTD will be estimated from the 
Bayesian model by utilizing all DLT-evaluable subjects. Please refer to Appendix C for 
more details on the BLRM and its operation characteristics. Before each DLRM, the 
above BLRM will be fitted with the prior distribution as specified in Appendix C. This 
model will only be used to aid DLRM dosing decision thus the recommendation of the 
model is non-binding in nature. 
9.6.3 
Laboratory Test Results 
9.6.3.1 
Chemistry and Hematology  
The analyses of safety laboratory endpoints will include summary statistics of baseline, 
post-baseline lab values at all the time points, change from baseline to post-baseline, 
post-baseline maximum/minimum and change from baseline to post-baseline 
maximum/minimum by dose level.  
Shifts tables indicating the change between the baseline and the worst post dose 
CTCAE grades based on CTCAE version 4.03 or later will be provided for selected 
laboratory parameters of interest. Subject incidence of worst post-baseline eosinophils 
counts by the laboratory normal range will be provided. 
Chemistry and hematology laboratory tests performed by local laboratories will be 
included in the analyses where applicable in cases where central laboratory 
values were not obtainable (i.e. due to Covid restrictions). 
A listing of subjects identified as potential Hy’s law cases (ALT or AST of 3xULN 
associated with total bilirubin  2xULN and ALP 2xULN at a visit) will be provided with 
relevant laboratory tests included in the listing.  


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9.6.4 
Vital Signs 
The analyses of vital signs will include summary statistics for baseline, post-baseline 
values at all the time points, change from baseline to post-baseline values at all the time 
points, post-baseline maximum/minimum and change from baseline to post-baseline 
maximum/minimum by dose level for systolic blood pressure, diastolic blood pressure, 
heart rate and temperature. 
9.6.5 
Physical Measurements 
The analyses will include summary statistics of weight at scheduled time-points and by 
dose level.  
9.6.6 
Electrocardiogram 
The ECG measurements will be performed as per standard of care for routine safety 
monitoring, rather than for purposes of assessment of potential QTc effect. Since these 
evaluations may not necessarily be performed under the rigorous conditions expected to 
lead to meaningful evaluation of QTc data; summaries and statistical analyses of ECG 
measurements are not planned, and these data would not be expected to be useful for 
meta-analysis with data from other trials. 
9.6.7 
Antibody Formation 
If needed, exploratory analyses of the relationship between safety and immunogenicity 
may be performed.  
9.6.8 
Exposure to Investigational Product 
The number of days on IP and the total dose of IP will be summarized using descriptive 
statistics. Number and percentage of subjects who missed IP doses due to COVID-19 
measures will be summarized. The final IPD list will be used to identify such subjects.  
A listing of the unique manufacturing lot numbers, and a listing of the subjects 
administered each manufacturing lot number will be provided 


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9.6.9 
Exposure to Concomitant Medication 
Number and proportion of subjects receiving medications/therapies of interest will be 
summarized by preferred term or category as coded by the World Health Organization 
Drug (WHODRUG) dictionary. 
Number and proportion of subjects who experienced a systemic corticosteroid 
dose reduction from baseline in subjects who were on systemic corticosteroid at 
baseline will be summarized by treatment group through week 52.  
9.7 
Other Analyses 
9.7.1 
Analyses of Pharmacokinetic or Pharmacokinetic/Pharmacodynamic 
Endpoints 
9.7.1.1 
Analysis of Pharmacokinetic Endpoint 
Pharmacokinetics analyses will be performed by Clinical Pharmacology, Modeling and 
Simulation (CPMS) group. The Pharmacokinetic Concentration Analysis set defined in 
Section 6.3.1 will be used in analyzing PK endpoints. Serum concentrations of 
efavaleukin alfa will be expressed in ng/mL. All concentrations below the limit of 
quantification or missing data will be labeled as such in the concentration data listings. 
Concentrations below the lower limit of quantification will be treated as zero in summary 
statistics. 
Actual dosing and sampling times and nominal doses (unless subjects had dosing 
errors, dosing changes, or dosing interruptions) will be used for individual 
concentration-time plots and calculation of PK parameters for each subject. The reasons 
for excluding any sample from the analyses will be provided. 
Individual concentration-time data will be tabulated and presented graphically. Summary 
of PK concentration over time and PK parameters will be provided. Mean 
concentration-time profiles for each dose will be provided. PK observations with missing 
concentration, missing dose, missing elapsed time will be excluded from PK statistical 
summary. PK parameters will be summarized for each dose using descriptive statistics, 
including subject numbers, mean, standard deviation, CV, median and range. 
9.7.1.2 
Analysis of Pharmacodynamic Endpoints 
The Pharmacodynamic (PD) Analysis set defined in Section 6.3.3 will be used. 
 
PD assessments include but are not limited to: 


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 Due to 
the skewed distribution of PD data, mean, standard deviation and standard error will be 
estimated based on log-transformed data, and the estimates will be back-transformed 
and presented, which are equivalent to geometric mean, geometric standard deviation 
and geometric standard error.  
To maintain the integrity of PD results, data collected at an end of treatment or end of 
extended treatment visit which is completed outside the upper limit of protocol defined 
window ( 9 days after the last dose date for QW cohorts and  16 days for Q2W 
cohorts) will not be included in the analysis. In addition, data collected at a visit after 
skipping one or more consecutive doses prior to that visit will be also excluded from 
analysis (the same window will be used as above i.e. ( 9 days after the last dose date 
for QW cohorts and  16 days for Q2W cohorts). 
9.7.1.3 
PK/PD Analysis 
Pharmacokinetic/pharmacodynamic modeling may be performed to explore relationship 
between efavaleukin alfa exposure and PD efficacy/safety endpoints by CPMS. 
9.7.2 
Analyses of Clinical Outcome Assessments 


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9.7.3 
Analyses of Biomarker Endpoints 
Not Applicable 
10. 
Changes From Protocol-specified Analyses 
The planned phase 1b interim analysis and phase 2 primary and final analyses are 
excluded from this analysis plan because the study is discontinued early. Instead, a final 
analysis will be conducted after the last subject in phase 1b part completes the study 
(including the treatment period and safety follow-up period).  


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11. 
Literature Citations / References 
efavaleukin alfa Protocol 20160283. Thousand Oaks, CA: Amgen Inc 
Bailey S, Neuenschwander B, Laird G, Branson M. (2009)  A Bayesian case study in 
oncology phase I combination dose-finding using logistic regression with covariates.  J 
Biopharm Stat.  19, 469-84. 
Brookmeyer R and Crowley J. (1982) A Confidence Interval for the Median Survival 
Time.  Biometrics, 38, 29-41. 
Jagasia MH; Greinix HT; Arora M, et al. (2015) National Institutes of Health Consensus 
Development Project on Criteria for Clinical Trials in Chronic Graft versus Host Disease: 
I. The 2014 Diagnosis and Staging Working Group Report. Biol Blood Bone Marrow 
Transpl. 21(3), 389-401. 
Kalbfleisch, J.D. and Prentrice, R.L. (1980) The Statistical Analysis of Failure Time Data, 
New York: John Wiley & Sons. 
Lee SJ; Wolff D; Kitko C; et al. (2014)  Measuring Therapeutic Response in Chronic 
Graft-versus-host Disease.  National Institutes of Health Consensus Development 
Project on Criteria for Clinical Trials in Chronic Graft-versus-Host disease:  IV.  The 2014 
Response. 
Lee SJ; Cook EF; Soiffer R; Antin JH.  (2002) Development and Validation of a Scale to 
Measure Symptoms of Chronic Graft-versus-Host Disease. Biol Blood Marrow 
Transplant. 8; 444-452. 
Neuenschwander B, Branson M, Gsponer T.  (2008) Critical aspects of the Bayesian 
approach to phase I cancer trials.  Statistics in Medicine.  27, 2420-39 
Ware JE. (2000)  SF-36 health survey update. Spine. 25(24), 3130-3139. 


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12. 
Prioritization of Analyses 
There is no prioritization of analyses. 
13. 
Data Not Covered by This Plan 
Exploratory data not included in this plan may be analyzed at a later date or may be 
analyzed by a different Amgen Department. 


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14. 
Appendices 
 


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Appendix A.  Technical Detail and Supplemental Information Regarding Statistical 
Procedures and Programs 
Imputation Rules for Partial or Missing Start Dates 
The reference date for the following rules is the date of first dose of IP. 
 
 
 
 
Start Date 
Stop Date 
Complete: 
yyyymmdd 
Partial: 
yyyymm 
Partial: 
yyyy 
Missing 
 1st 
dose 
 1st 
dose 
 1st 
dose 
yyyym
m 
 1st 
dose 
yyyym
m 
 1st 
dose 
yyyy 
 1st 
dose 
yyyy 
 
Partial: 
yyyymm 
 1st 
dose 
yyyymm 
 
2 
1 
n/a 
1 
n/a 
1 
1 
 1st 
dose 
yyyymm 
2 
2 
2 
2 
2 
2 
Partial: 
yyyy 
 1st 
dose 
yyyy 
 
3 
1 
 
3 
1 
n/a 
1 
1 
 1st 
dose 
yyyy 
3 
3 
3 
3 
3 
Missing 
4 
1 
4 
1 
4 
1 
1 
1Impute the date of first dose;  
2Impute the first of the month;  
3Impute January 1 of the year;  
4Impute January 1 of the stop year; 
Note: For subjects who were never treated (first dose date is missing), partial start dates 
will be set to the first day of the partial month or first day of year if month is also missing. 
Imputation Rules for Partial or Missing Stop Dates 
Initial imputation 
 
If the month and year are present, impute the last day of that month. 
 
If only the year is present, impute December 31 of that year. 
 
If the stop date is entirely missing, assume the event or medication is ongoing. 
If the imputed stop date is before the start date, set stop date to missing. 


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If the imputed stop date is after the death date, impute as death date. 
Imputation Rules for Partial or Missing Death Dates 
If death year and month are available but day is missing: 
 
If yyyymm for the date last known to be alive equals yyyymm for death date, set 
death date to the day after the date last known to be alive. 
 
If yyyymm for the date last known to be alive is less than the yyyymm for death date, 
set death date to the first day of the death month. 
 
If yyyymm for the date last known to be alive is greater than yyyymm for death date, 
assume date last known to be alive is in error, set death date to the first day of the 
death month. 
If month and day are missing and year of death is known: 
 
If yyyy for the date last known to be alive equals yyyy for death date, set death date 
to the day after last known to be alive date. 
 
If yyyy for the date last known to be alive is less than yyyy for death date, set death 
date to the first day of the death year. 
 
If yyyy for the date last known to be alive is greater than yyyy for death date, assume 
date last known to be alive is in error, set death date to the first day of the death 
year. 
If a death date is totally missing: 
 
Set death date to the day after the date last known to be alive. If the date last known 
to be alive is a partial date, set it to the first day of the month last known to be alive 
or first day of the year last known to be alive if month is also missing. 
 


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Appendix B.  Reference Values/Toxicity Grades  
The Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 will be 
used and is available at the following location 
Common Terminology Criteria for Adverse Events (CTCAE) | Protocol Development | 
CTEP (cancer.gov) 


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Appendix C.  Bayesian Logistic Regression Model 
The study will use BLRM to guide dose escalation. The MTD target toxicity probability 
interval for DLT is (0.20, 0.30), and TPIs of (0.30, 0.60) and (0.60, 1.00) are defined as 
excessive and unacceptable, respectively. The design seeks to identify a dose most 
likely to have a DLT rate in the target TPI, but with overdose control that limits the 
possibility the dose has an excessive or unacceptable DLT rate (Babb et al, 1998).   
Let 𝒅(𝑑1 , … , 𝑑𝑘 ) denote the vector of all efavaleukin alfa doses to be studied in the 
study. The probability of a DLT at dose level 𝑑𝑖, 𝑖1, … , 𝑘 is assumed to follow a Bernoulli 
distribution with probability 𝑝𝑖 where the logit of 𝑝𝑖 increases linearly with the log of the 
standardized dose in the following 2-parameter logistic model: 
log [
𝑝𝑖
1 −𝑝𝑖
] 𝑙𝑜𝑔𝑖𝑡(𝑝𝑖)log[𝑎] exp(log[𝑏]) log (
𝑑𝑖
max (𝒅)) 
where a and b are random variables and 𝑑𝑖 is dose level represented by predicted 
). 𝑑𝑘 is an 
additional dose assuming Treg concentration 
 that’s higher than the currently 
planned doses. Thus 𝒅
. If additional dose cohorts were 
added during study conduct (e.g., decision following a DLRM), the value of 𝒅 will be 
updated.  
A minimally informative prior distribution (Neuenschwander et al, 2008) was selected for  
𝜃(log[𝑎] , log [𝑏]), where the probability that the true DLT rate is  0.20 at the lowest 
dose is 0.90 and the probability the true DLT rate is  0.50 at the maximum dose is 0.90. 
Median values for 𝑝𝑖 were interpolated per the logistic model. For each  𝑑𝑖, 2 quantiles 
for 𝑝𝑖were selected from a minimum informative Beta distribution with the target median.  
This set of quantiles fully specified a target prior for theta. A bivariate normal distribution 
for 𝜃 was assumed where (log[𝑎]) has a normal distribution with mean ma and standard 
deviation sa, and (log[𝑏]) has a normal distribution with mean mb and standard deviation 


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sb, and r is the correlation between log[𝑎] and log[𝑏]. Numerical integration with the R 
“integrate” function was used to calculate Pr[𝑝𝑖𝑞(𝑑𝑖) where 𝑞(𝑑𝑖) is a quantile for dose 
𝑑𝑖. An optimal bivariate normal distribution was estimated that achieved the minimum 
sum of squared difference between achieved and specified quantiles across all doses 
using a non-linear optimization with the R “optim” function. The bivariate normal 
distribution prior solution has ma  -1.283, sa  1.002, mb  0.280, sb   0.770, and r  -
0.568. 
The operating characteristics of the BLRM model were evaluated via simulation with 
cohort size of 3. All simulated studies started with an initial dose strength of 
 and 
subsequent doses were selected based on the following rules: 
 
After each cohort, the next dose is the one with the highest probability of the target 
TPI, but with a less than 0.25 probability of an excessive or unacceptable TPI. 
 
If  1 subject has a DLT at a dose, then no higher dose can be evaluated unless 
there are at least 6 evaluable subjects at this lower dose.   
No skipping of planned dose is allowed. 
The dose escalation will be stopped given one or more of the following conditions: 
 
The model recommends the same dose  3 times (not necessarily sequentially) 
 
A maximum of 24 subjects is evaluated. 
The design was evaluated for three possible dose-response scenarios consistent with 
the design’s model:  “Low”, “Mid”, and “High” MTD. The possible dosing strength in the 
simulation is
, where 
and 
 was added to simulate 
the “High MTD” scenario where the true MTD exceeds the currently planned dose. See 
Table 2 for the probability profiles of the three scenarios (acceptable MTDs (between 0.2 
to 0.3) are marked bold)  


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Table 2.  Probability Profile of Low, Mild and High Scenario 
Dosing 
Strength 
Probability of DLT 
Low MTD 
Mid MTD 
High MTD 
0.2 
 0.1 
0.01 
0.3 
 0.2 
0.05 
0.3 
0.2 
 0.05 
0.4 
0.3 
0.1 
0.5 
0.4 
0.2 
0.6 
0.5 
0.3 
For each dosing profile, 
 simulated trial data was generated and the BLRM model 
was used to guide the dose escalation. The simulation results are summarized in 
Table 3 
Table 3.  Summarized Simulation Results for BLRM  
 
Low MTD 
Mid MTD 
High MTD 
N  
14.8 (6, 21)* 
19.7 (18, 24) 
23.0 (24, 24) 
MTD dose 
129.1 (
) 
200.4 (
) 
416.8 (
) 
 select acceptable 
MTD 
50.6 
62.2 
86.8 
 all dose too toxic 
39.2 
12.0 
0 
Study  of DLTs   
4.1 (3, 5) 
4.2 (4, 5) 
2.8 (2, 4) 
Study prob. of DLT 
33.1  
23.3 
11.9 
* all continuous data in this table is reported in mean (Q1, Q3) 


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Appendix D.  Disease Related Events Table 
Organ System 
Disease Related Event 
Skin 
Scleroderma (superficial or fasciitis), lichen 
planus, vitiligo, scarring alopecia, hyperkeratosis 
pilaris, contractures from skin immobility, nail bed 
dysplasia 
Mucous membranes 
Lichen planus, non-infectious ulcers, corneal 
erosions/non-infectious conjunctivitis, xerostomia, 
keroconjunctivitis sicca 
GI tract 
Esophageal strictures, steatorrhea, anorexia, 
malabsorption, weight loss, abdominal pain 
Liver 
None  
GU tract 
Vaginal stricture, lichen planus  
Musculoskeletal /Serosa 
Non-septic arthritis, myositis, myasthenia, 
polyserositis, contractures from joint 
immobilization 
Hematologic 
None 
Lung 
Bronchiolitis obliterans  


Product:  efavaleukin alfa 
Protocol Number:  20160283 
Date:  31 January 2023 
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Product:  efavaleukin alfa 
Protocol Number:  20160283 
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Product:  efavaleukin alfa 
Protocol Number:  20160283 
Date:  31 January 2023 
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Protocol Number:  20160283 
Date:  31 January 2023 
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Protocol Number:  20160283 
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Date:  31 January 2023 
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Appendix G.  Analytical Windows 
The last visit with non-missing assessment prior to first dose will be defined as a 
baseline visit (unless specified otherwise) and the analysis visit name will be “Baseline”.  
For any visit up to Day 1 pre-dose which is not a baseline visit, the analysis visit will be 
‘Pre-Analysis’. For Day 1 post-dose visits, and safety follow-up visit, the analysis visit will 
be same as the scheduled visit. For any unscheduled visit post safety follow-up visit, the 
analysis visit will be considered as safety follow-up visit. For post-dose assessments on 
Day 29 (the day corresponding to Week 4 dosing) and Day 113 (the day corresponding 
to week 16 dosing), the analysis visit will be same as the scheduled visit. Remaining 
visits (scheduled visit, unscheduled visit, progressive disease visit, or end of treatment 
visit) after Day 1 for any assessment will be mapped to the analysis visit based on visit 
windows defined in the tables below for that assessment. Only visits applicable for that 
assessment and phase of the study as per the Schedule of Activities tables in the study 
protocol will be considered for analysis. 
Data collected through central lab and local lab will both be mapped into analysis visit 
windows. The local lab data can only be used in analysis when there is no central lab 
data available in the analysis visit window.   
If more than one visit with non-missing data falls within an analysis visit window, the visit 
closest to the target day will be considered for analysis. If two visits are equidistant from 
the target day, the latest visit (or time if on the same day) will be considered. If more 
than one evaluation has same date and time (for chemistry, hematology or 
pharmacodynamics results), the value with the smallest accession number will be 
considered. 
Analysis visit windows for selected assessments are included in tables below. For 
remaining assessments, no visit window will be applied. Day 29 and Day 113 used in 
Study day window calculation in the tables below is the respective study day when Week 
4 dose and Week 16 dose was received. If that dose is missing, then 29 and 113 is used 
for respective calculation. 
 
Vitals 
Analysis Visit 
Target 
Day 
Study Day Window 


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Week 1, Day 2 
2 
2 
Week 1, Day 3  
3 
3 
Week 1, Day 4 
4 
4-6 
Week 1, Day 8  
8 
7-9 
Week 1, Day 11 
11 
10-12 
Week n, Day 7*n1 
 (n  2, 3, 4, 5, 6, 7,8, 9, 10, 
11, 12, 13, 14) 
7n1 
Target day -2, Target day 4 
Week 15, Day 106 
106 
104, Day 113-3 
Week 16, Day 113 Pre-dose 
113 
Day 113-2, Day 113 
Week 16, Day 114 
114 
Day 113  1 
Week 16, Day 115 
115 
Day 113  2 
Week 16, Day 116 
116 
Day 113  3 
Week 17, Day 120 
120 
Day 113  4, 124 
Week 18, Day 127 
127 
125-131 
Week 20, Day 141 
141 
132-148 
Week n, Day 7*n1 
 (n  22, 24, 26,..  to 258 in 
increments of 2) 
7n1 
Target day -6, Target day 7 
Week 260, Day 1821 
1821 
1814 


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Chemistry and Hematology, Weight 
Week 1, Day 2 
2 
2-3 
Week 1, Day 8 
8 
4-12 
Week n, Day 7*n1  
(n  2, 3, 4, 5, 6, 7) 
7*n1 
Target day -2, Target day 4 
Week 8, Day 57 
57 
55-71 
Week n, Day 7*n1  
(n12, 16, 20, …, to 104 in 
increments of 4) 
7*n1 
 
Target day -13 days, Target day  14 days 
 
Week 108, Day 757 
757 
744, 764 
Week n, Day 7*n1  
(n110, …, to 258 in 
increments of 2) 
7*n1 
 
Target day -6 days, Target day  7 days 
 
Week 260, Day 1821 
1821 
1815, SFU -1 if SFU* is available, otherwise 
1814 
*study day corresponding to safety follow-up visit assessment 
 
 
Pharmacodynamic assessments 
Week 1, Day 2 
2 
2-3 
Week 1, Day 4 
4 
4-6 
Week 1, Day 8 
8 
7-9 
Week 1, Day 11 
11 
10-12 
Week 2, Day 15 
15 
13-19 


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Week 3, Day 22 
22 
20, Day 29 - 3 
Week 4, Day 29 
29 
Day 29 -2, Day 29 
Week 4, Day 30 
30 
Day 29 1   
Week 4, Day 32 
32 
Day 29  2, Day29 4  
Week 5, Day 36 
36 
Day 29  5, 40 
Week n, Day 7*n1  
 (n  6,7,8,9,10,11) 
7*n1 
Target day -2, Target day 4 
Week 12, Day 85 
85 
83, 92 
Week 14, Day 99 
99 
93, Day 113 -7 
Week 16, Day 113 
113 
Day 113- 6, Day 113 
Week 16, Day 114 
114 
Day 113 1 
Week 16, Day 116 
116 
Day 113 2, Day 113 4 
Week 17, Day 120 
120 
Day 113 5, 124 
Week 18, Day 127 
127 
125- 134 
Week n, Day 7*n 1 
(n 20, 22, ..to 50 in 
increments of 2 ) 
7*n1 
Target day -6 days, Target day  7 days 
Week 52, Day 365 
365 
359-379 
Week n, Day 7*n 1 (n 56, 
60, 64, …, to 104 in 
increments of 4) 
7*n1 
Target day - 13 days, Target day  14 days 
Week 108, Day 757 
757 
744, 764 


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Week n, Day 7*n1  
(n110, …, to 258 in 
increments of 2) 
7*n1 
 
Target day -6 days, Target day  7 days 
 
Week 260, Day 1821 
1821 
1814 
 
Antibody assessments 
Week 2, Day 15 
15 
2- 22 
Week 4, Day 29 
29 
23- 43 
Week n, Day 7*n 1 (n 8, 12, 
16,…, to 104 in increments of 
4) 
7*n1 
Target day -13 days, Target day  14 days 
Week 108, Day 757 
757 
744, 764 
Week n, Day 7*n1  
(n110, …, to 258 in 
increments of 2) 
7*n1 
 
Target day -6 days, Target day  7 days 
 
Week 260, Day 1821 
1821 
1814 


Product:  efavaleukin alfa 
Protocol Number:  20160283 
Date:  31 January 2023 
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