Clinical trial NCT01767857
Conditions: Metastatic Colorectal Cancer
Keywords: Pivotal Colorectal Survival Phase 3
Sponsor: Janssen Research & Development, LLC
Start date: 2013-03-31; Completion date: 2017-06-30
Enrollment: 643 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine if the True Human Monoclonal antibody Xilonix (MABp1) can prolong the life of colorectal carcinoma patients that are refractory to standard therapy.

Detailed description:
In the setting of refractory, metastatic disease a complete resolution of tumor burden is not a reasonable expectation. Instead, the primary goal of anti-tumor therapy at this stage is to eliminate or reduce the symptomatic effects of the tumor, while trying to prolong survival for as long as possible. Due to treatment related morbidity however, few treatment modalities are ideal for this objective. Even with the most recent targeted agents (such as multi-kinase inhibitors), drug related toxicities frequently lead to relatively short treatment durations. With discontinuation of therapy, disease progression is uncontrolled and prognosis is poor.

New agents that control disease progression-while improving tumor-related symptoms, rather than causing significant therapy related morbidity-are vitally needed to treat patients with advanced cancer, including those with colorectal cancer. An approach has been taken to develop such an agent using a monoclonal antibody to block the chronic inflammation involved in both malignant disease progression and constitutional symptoms.

Xilonix™ is expected to inhibit tumor growth and metastasis by interrupting crucial signals that drive angiogenesis and invasiveness. The antibody therapy may also block tumor microenvironment infiltration by leukocytes (such as myeloid suppressor cells) that suppress antitumor immunity, enabling better host immune control of the disease. In addition to local effects on the tumor, Xilonix™ is expected to work systemically to correct the metabolic dysregulation, fatigue and anxiety mediated by chronic inflammatory signaling to the central nervous system.

Arms: arm 1: MABp1 administered IV every two weeks, plus best supportive care arm 2: Placebo administered IV every two weeks, plus best supportive care
Interventions: intervention 1: Xilonix intervention 2: Placebo
Intervention descriptions: intervention 1: Xilonix is a True Human Monoclonal Antibody targeting Interleukin 1 alpha, and is administered intravenously every 2 weeks with best supportive care until clinical or radiographic progression. intervention 2: Placebo plus best supportive care will be administered intravenously every 2 weeks until clinical or radiographic progression.

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Trial Protocol 
A Phase III Double-blinded, Placebo 
Controlled Study of Xilonix™ for Improving 
Survival in Metastatic Colorectal Cancer  
 
SPONSOR 
XBiotech USA Inc 
 
 
 
 
 
 
 
 
05 June 2017 
NCT01767857


XBIOTECH USA INC.              ADVANCED COLORECTAL CANCER               PROTOCOL 2012-PT023 V3.7 
CONFIDENTIAL                                        05 June, 2017                                            PAGE 2 of 74 
 
Table of Contents 
Basic Information ...................................................................................................................................... 4 
Investigator/Sponsor Signatures............................................................................................................ 5 
Clinical Protocol Synopsis ....................................................................................................................... 6 
Abbreviations ........................................................................................................................................... 12 
1. BACKGROUND .................................................................................................................................... 13 
1.1 
TARGETING INTERLEUKIN-1 ALPHA (IL-1α) .................................................................................. 13 
1.2 PLEIOTROPIC MECHANISM OF ACTION ................................................................................................. 14 
1.3 REVIEW OF THE IL-1 SYSTEM .................................................................................................................... 17 
1.4 OBSERVATION IN PREVIOUS STUDY: MABP1 INCREASED LEAN BODY MASS IN 
PATIENTS WITH REFRACTORY METASTATIC CANCER ......................................................................... 18 
1.5 ANALYSIS OF COLORECTAL COHORT ...................................................................................................... 20 
1.6 QUALITY OF LIFE ANALYSIS ........................................................................................................................ 21 
1.7 CORRELATIVE ANALYSIS ............................................................................................................................... 21 
2. INVESTIGATIONAL PRODUCT....................................................................................................... 25 
2.1 ACTIVE INGREDIENT, PHARMACOLOGIC CLASS, STRUCTURE ................................................... 25 
2.2 DRUG PRODUCT (XILONIX™) DESCRIPTION ........................................................................................ 26 
2.3 DESCRIPTION AND COMPOSITION OF PLACEBO PRODUCT ........................................................ 26 
2.4 STORAGE ................................................................................................................................................................ 27 
2.5 STABILITY ............................................................................................................................................................. 27 
2.6 METHOD OF ADMINISTRATION ................................................................................................................. 27 
2.7 AGENT ORDERING ............................................................................................................................................ 28 
2.8 POTENTIAL DRUG INTERACTIONS ........................................................................................................... 28 
2.9 PROHIBITED AND RESTRICTED THERAPIES ...................................................................................... 28 
3. STUDY DESIGN AND OBJECTIVES ................................................................................................ 29 
4. ELIGIBILITY CRITERIA .................................................................................................................... 30 
4.1 INCLUSION CRITERIA ...................................................................................................................................... 30 
4.2 EXCLUSION CRITERIA ..................................................................................................................................... 31 
5. TREATMENT PLAN ........................................................................................................................... 33 
5.1 DOSE MODIFICATIONS ................................................................................................................................... 33 
5.2 DISCONTINUATION OF THERAPY ............................................................................................................. 34 
5.3  EMERGENCY UNBLINDING.......................................................................................................................... 34 
5.4 STUDY PROCEDURES ....................................................................................................................................... 35 
5.4 STUDY CALENDAR ............................................................................................................................................ 41 
6. CORRELATIVE STUDIES ............................................................................................................. 44 
6.1 PHARMACOKINETICS (PK) SAMPLE COLLECTION ........................................................................... 44 
7. CRITERIA FOR EVALUATION ......................................................................................................... 44 
7.1 SAFETY DATA MONITORING........................................................................................................................ 44 
7.2 MEASUREMENT OF EFFECT ........................................................................................................................ 44 
7.3 RADIOGRAPHIC ASSESSMENT OF BODY COMPOSITION ................................................................ 44 
7.4 QUALITY OF LIFE ASSESSMENT ................................................................................................................. 45 
7.5 RADIOGRAPHIC MEASUREMENT OF TUMOR SIZE ........................................................................... 46 
7.5.1 Immune Related Response Criteria: ............................................................................................. 47 


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8. SAFETY AND TOLERABILITY......................................................................................................... 49 
8.1 ONCOLOGY (SOLID TUMOR) DATA: .......................................................................................................... 49 
8.2 REFERENCE SAFETY INFORMATION: POTENTIAL ADVERSE REACTIONS ........................... 54 
9. ADVERSE EVENTS ............................................................................................................................. 57 
9.1 DEFINITION OF ADVERSE EVENT (AE) .................................................................................................. 57 
9.2 DEFINITION OF SERIOUS ADVERSE EVENT (SAE)............................................................................ 57 
9.3 RECORDING OF ADVERSE EVENTS ........................................................................................................... 57 
9.4 EVALUATING ADVERSE EVENTS ............................................................................................................... 58 
9.5 ASSESSMENT OF CAUSALITY ....................................................................................................................... 58 
9.6 REPORTING REQUIREMENTS ...................................................................................................................... 58 
9.7 SAFETY LEAD IN PLAN ................................................................................................................................... 58 
10. STATISTICAL ANALYSIS .......................................................................................................... 60 
10.1 STUDY DESIGN ................................................................................................................................................. 60 
10.2 STUDY ENDPOINTS ........................................................................................................................................ 60 
10.2.1 Primary Efficacy Endpoint: .......................................................................................................... 60 
10.2.2 Secondary Endpoints: ..................................................................................................................... 60 
10.2.3 Exploratory Endpoint: .................................................................................................................... 60 
10.2.4 Safety Endpoint: ............................................................................................................................... 60 
10.3 SAMPLE SIZE AND POWER ........................................................................................................................ 61 
10.4 STATISTICAL ANALYSIS PLAN.................................................................................................................. 61 
11. STUDY MANAGEMENT AND ADMINISTRATION ........................................................... 65 
11.1 ETHICAL CONDUCT OF STUDY (GCP) ................................................................................................... 65 
11.2 IRB AND ETHICS COMMITTEE APPROVAL ......................................................................................... 65 
11.3 PROTOCOL MODIFICATIONS ..................................................................................................................... 65 
11.4 SUBJECT INFORMATION AND CONSENT ............................................................................................ 65 
11.5 DATA PROTECTION AND CONFIDENTIALITY ................................................................................... 66 
11.6 STUDY REPORT AND PUBLICATIONS ................................................................................................... 66 
11.7 STUDY FILES AND RETENTION OF RECORDS .................................................................................. 66 
11.8 CASE REPORT FORMS ................................................................................................................................... 66 
11.9 DRUG ACCOUNTABILITY ............................................................................................................................. 67 
11.10 INSPECTIONS ................................................................................................................................................. 67 
11.11 ACCESS TO INFORMATION FOR MONITORING .............................................................................. 67 
11.12 STUDY DISCONTINUATION ..................................................................................................................... 68 
APPENDIX A ........................................................................................................................................... 69 
APPENDIX B ........................................................................................................................................... 70 
REFERENCES............................................................................................................................................ 72 
 
 
 


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Basic Information 
 
STUDY TITLE: Phase III Double-blinded, Placebo Controlled Study of Xilonix™ for 
Improving Survival in Metastatic Colorectal Cancer 
 
INVESTIGATIONAL PRODUCT: 
Xilonix™ 
 
IND Number  
 
 
 
114,759 
 
 
 
 
PROTOCOL NUMBER: 
 
 
2012-PT023  
 
 
 
PROTOCOL VERSION / DATE:  
Version 3.7 / June 5th, 2017  
 
 
SPONSOR:  
 
 
 
XBiotech USA, Inc.  
8201 E Riverside Drive 
Building 4, Suite 100 
Austin, Texas 78744 U.S.A. 
Phone: 512-386-5107 
 
 
 
SPONSOR’S MEDICAL OFFICER: 
Michael Stecher M.D. 
XBiotech USA, Inc.  
8201 E Riverside Drive 
Building 4, Suite 100 
Austin, Texas 78744 U.S.A. 
Phone: 512-386-2998 
 
STUDY CHAIR  
 
  
 
 
 
 
 
George Fisher M.D., Ph.D. 
 
 
 
 
 
 
Associate Professor of Medicine 
 
 
 
 
 
 
Stanford University School of Medicine 
 
 
 
 
 
 
875 Blake Wilbur Drive 
 
 
 
 
 
 
Stanford, CA 94305-5826 
 
 
 
 
 
 
Phone: 650-725-9057 
 
 
 
 
 
 
 
 
 


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Investigator/Sponsor Signatures 
 
STUDY TITLE: Phase III Double-blinded, Placebo Controlled Study of Xilonix™ for 
Improving Survival in Metastatic Colorectal Cancer 
STUDY PRINCIPAL INVESTIGATOR SIGNATURE:  
I have read the protocol and appendices. I understand the contents and intend to comply fully 
with all requirements and the applicable current local and international regulations and 
guidelines. No changes will be made without formal authorization by XBiotech USA, Inc., in the 
form of a protocol amendment. 
 
 
INVESTIGATOR SIGNATURE: 
 
 
_____________________________________________  
Printed name of Investigator  
 
 
_____________________________________________  
Signature  
 
 
_____________________________________________  
Date  
 
 
SPONSOR SIGNATURE:  
 
XBiotech USA, Inc. 
 
Michael Stecher M.D., Medical Director 
 
 
____________________________________________  
Signature 
 
 
____________________________________________  
Date 


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Clinical Protocol Synopsis 
 
Study Title:    
 
 
 
 
Phase III Double-blinded, Placebo Controlled Study of Xilonix™ for Improving Survival in 
Metastatic Colorectal Cancer  
 
Sponsor:   
 
 
 
 
 
XBiotech USA, Inc. 
 
Study Chair:   
 
 
George Fisher M.D., Ph.D. 
 
Sample Size:  
 
 
 
Approximately 600 subjects. 
 
 
Approximate Duration: 
 
The total study duration is 18 months. The duration of subject participation in the evaluation of 
body composition is approximately 77 days (including a screening period of 14 days and a 
treatment/follow up period of 63 days). Subjects with radiographic evidence of progression, as 
assessed by the Immune Related Response Criteria (irRC) should be discontinued from therapy. 
 
Study Objectives: 
 
Primary Efficacy Endpoint 
 
• 
Overall survival (OS) will be the primary endpoint of this study, which will be measured 
from the date of randomization until death or last follow-up.  
 
Secondary Efficacy Endpoints 
 
• 
Secondary efficacy variables will include change in lean body mass (LBM) measured by 
dual-energy X-ray absorptiometry (DEXA) scans, change in Quality of Life assessed 
through the cancer-specific EORTC QLQ-C30 questionnaire, stabilization of platelet 
counts, progression free survival (PFS), objective response rate (ORR) and disease 
control rate (DCR). 
 


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Study Rationale: 
 
In the setting of refractory, metastatic disease a complete resolution of tumor burden is not a 
reasonable expectation. Instead, the primary goal of anti-tumor therapy at this stage is to 
eliminate or reduce the symptomatic effects of the tumor, while trying to prolong survival for as 
long as possible. Due to treatment related morbidity however, few treatment modalities are ideal 
for this objective. Even with the most recent targeted agents (such as multi-kinase inhibitors), 
drug related toxicities frequently lead to relatively short treatment durations. With discontinuation 
of therapy, disease progression is uncontrolled and prognosis is poor. 
New agents that control disease progression—while improving tumor-related symptoms, rather 
than causing significant therapy related morbidity—are vitally needed to treat patients with 
advanced cancer, including those with colorectal cancer. An approach has been taken to develop 
such an agent using a monoclonal antibody to block the chronic inflammation involved in both 
malignant disease progression and constitutional symptoms. 
Xilonix™ is expected to inhibit tumor growth and metastasis by interrupting crucial signals that 
drive angiogenesis and invasiveness. The antibody therapy may also block tumor 
microenvironment infiltration by leukocytes (such as myeloid suppressor cells) that suppress 
antitumor immunity, enabling better host immune control of the disease. In addition to local 
effects on the tumor, Xilonix™ is expected to work systemically to correct the metabolic 
dysregulation, fatigue and anxiety mediated by chronic inflammatory signaling to the central 
nervous system. 
We have reported the first observation that increases in lean body mass (LBM) in patients with 
advanced metastatic disease are associated with a very substantial survival benefit. In the recent 
clinical study where these observations were made, patients were treated with an anti-IL-1α 
therapeutic antibody (Xilonix™) to block tumor-related inflammation. Dual energy X-ray 
absorptiometry was used to accurately and objectively measure changes in body mass, and 
discriminate between changes in lean mass (i.e. muscle) and fat. LBM increased an average of 
1.9±2kg within 8 weeks in 70% of the per-protocol population (p<0.001). In the colorectal 
carcinoma cohort, patients that gained lean body mass had dramatic improvement in survival 
(19.3 months vs 6.6 p=0.098) compared to those that lost lean mass1. 
Dramatic improvement in survival in patients with increasing LBM after treatment with an anti-
IL-1α therapeutic antibody suggests new hope for treating patents that are currently considered 
refractory. The use of this antibody monotherapy to target chronic inflammation is proposed as a 
safe, effective treatment for patients with metastatic colorectal cancer.  
 
Trial Design: 
 
This is a phase III, multicenter, double blind, randomized, placebo controlled pivotal trial of the 
True Human monoclonal antibody MABp1 (Xilonix™) in subjects with metastatic colorectal 
cancer who are refractory to standard therapy. 
 
• 
Enrolled subjects will be randomized (2:1) to receive either MABp1 plus best supportive 
care (BSC) versus placebo plus BSC. 
• 
BSC is defined as those measures intended to provide palliation of symptoms and 
improve quality of life. This includes, but is not limited to, antibiotics, anti-emetics, 
narcotics, and parenteral nutrition. 


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• 
Subjects randomized to MABp1 or placebo will receive 7.5 mg/kg of study drug via 
intravenous infusion once every 2 weeks (one cycle).  
• 
Study drug will be administered under close observation in a facility equipped to handle 
medical emergencies. Subjects must be observed for at least 1 hour with stable vital signs 
following the end of the infusion.   
• 
Efficacy will be assessed by comparing overall survival (OS) between the MABp1 and 
placebo groups.   
• 
Secondary endpoints will include change in lean body mass and quality of life from 
screening to the cycle 5 assessment. Other secondary endpoints will be progression-free 
survival, objective response rate (ORR), disease control rate (DCR), and stabilization of 
platelet counts. Lean body mass measurements will be obtained through the use of dual-
energy X-ray absorptiometry (DEXA) scans. Quality of life will be assessed with the 
EORTC QLQ-C30 (v. 3). Response and progression will be evaluated using the Immune 
Related Response Criteria (irRC). 
• 
Safety assessments will include physical examinations, vital signs, standard clinical 
laboratory evaluations (blood chemistry, urinalysis, and hematology), allergic reaction 
monitoring and adverse event monitoring.  
• 
Pharmacokinetics samples will be taken in all patients. The pharmacokinetics of MABp1 
in plasma will be randomly analyzed. Plasma samples will also be randomly monitored 
for the development of anti-MABp1 antibodies.  If the study meets the primary endpoint, 
then all samples will be tested. 
 


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Inclusion Criteria:  
 
No waivers/exemptions will be granted for protocol inclusion/exclusion criteria. 
 
Subjects are included in the study if they meet all of the following criteria: 
 
1. Subjects with pathologically confirmed colorectal carcinoma that is metastatic or 
unresectable and which is refractory to standard therapy. To be considered refractory, a 
subject must have experienced progression (or intolerance) after treatment with at least 
all of the following agents: oxaliplatin, irinotecan, flouropyrimidine, and cetuximab or 
panitumumab if KRAS wildtype.    
2. Subjects will not be treated with any radiation, chemotherapy, or investigational agents 
while enrolled in this protocol.   
3. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2. 
4. At least 2 weeks since the last previous cancer treatment including:  chemotherapy, 
radiation therapy, immunotherapy, surgery, hormonal therapy, or targeted biologics and 4 
weeks for patients who received treatment immediately prior to the study with anti-IL-1 
or anti-TNF agents. 
5. Age ≥ 18 years, male or female subjects. 
6. Serum potassium and magnesium levels within Central Lab normal limits. Total serum 
calcium or ionized calcium level must be greater than or equal to the lower limit of 
normal. Subjects with low potassium, calcium and magnesium levels may be replenished 
to allow for protocol entry. 
7. Adequate renal function, defined by serum creatinine ≤ 1.5 x Central Lab ULN. 
8. Adequate hepatic function defined as:  
• 
total bilirubin ≤ 1.5 times the Central Lab ULN 
• 
alanine aminotransferase (ALT) ≤ 2.0 times the Central Lab ULN 
Exception: subjects with known liver metastases: ≤ 3.0 times the 
institutional ULN for ALT.  
9. Adequate bone marrow function as defined as: 
• 
absolute neutrophil count (neutrophil and bands) of ≥ 1,500/mm3 (≥ 1.5 x 109/L) 
• 
platelet count of ≥ 100,000/mm3 (≥ 100 x109/L) 
• 
hemoglobin of ≥ 9 g/dL 
10. For women of childbearing potential (WOCBP), a negative serum pregnancy test result at 
Screening and monthly thereafter.  
For women who are not postmenopausal (24 months of amenorrhea) or surgically sterile 
(absence of ovaries and/or uterus): agreement to use adequate methods of contraception, 
during the treatment period and for at least 1 month after the last dose of study drug.  
Acceptable contraceptive measures include: 
- 
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 hormone-
releasing system(IUS) 
- 
Barrier or sterilization methods such as condoms, bilateral tubal occlusion, 
vasectomized partner or sexual abstinence  
 


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For men: agreement to use a barrier method of contraception during the treatment period 
and for at least 1 month after the last dose of study drug  
 
11. Signed and dated institutional review board (IRB)-approved informed consent before 
any protocol-specific screening procedures are performed. 
12. Patients enrolled must, in the Investigator’s judgment, be healthy enough to stay on 
the clinical trial for three months. 
 


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Exclusion Criteria: 
 
Subjects with ANY of the following will be excluded from the study: 
 
1. Mechanical obstruction that would prevent adequate oral nutritional intake. 
2. Serious uncontrolled medical disorder, or active infection, that would impair the ability of 
the patient to receive protocol therapy.  
3. Uncontrolled or significant cardiovascular disease, including:  
• 
A myocardial infarction within the past 6 months. 
• 
Uncontrolled angina within the past 3 months.  
• 
Congestive heart failure within the past 3 months, defined as New York Heart 
Association (NYHA) Classes II or higher. 
• 
Diagnosed or suspected congenital long QT syndrome.  
• 
Any history of clinically significant ventricular arrhythmias (such as ventricular 
tachycardia, ventricular fibrillation, Wolff-Parkinson-White (WPW) syndrome, 
or torsade de pointes).  
• 
Any history of second or third degree heart block (may be eligible if currently 
have a pacemaker). 
• 
Uncontrolled hypertension (blood pressure >140 mm Hg systolic and >90 mm 
Hg diastolic).  
4. Dementia or altered mental status that would prohibit the understanding or rendering of 
informed consent. 
5. Subjects who have not recovered from the adverse effects of prior therapy at the time of 
enrollment to ≤ grade 1; excluding alopecia and grade 2 neuropathy. 
6. Immunocompromised subjects, including subjects known to be infected with human 
immunodeficiency virus (HIV). 
7. Known hepatitis B surface antigen and/or positive hepatitis C antibody and presence of 
hepatitis C RNA. 
8. History of tuberculosis (latent or active) or known positive Interferon-gamma release 
assay (IGRA). 
9. Receipt of a live (attenuated) vaccine within 1 month prior to Screening. 
10. Subjects with history of hypersensitivity to compounds of similar chemical or biologic 
composition of Xilonix™. 
11. Women who are pregnant or breastfeeding. 
12. WOCBP or men whose sexual partners are WOCBP who are unwilling or unable to use 
an acceptable method of contraception for at least 1 month prior to study entry, for the 
duration of the study, and for at least 1 month after the last dose of study medication. 
13. Weight loss >20% in the previous 6 months. 
14. History of progressive multifocal leukoencephalopathy or other demyelinating disease 
15. Subjects on immunosuppressive therapy, including transplant patients 
 
 


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Abbreviations 
 
AE 
 
Adverse event 
ALT 
 
Alanine aminotransferase (ALT, SGPT) 
PT/aPTT  
Prothrombin Time/Activated Partial Thromboplastin Time 
ALP 
 
Alkaline phosphate 
BMI 
 
Body Mass Index 
BP 
 
Blood pressure 
CACS 
 
Cancer Anorexia Cachexia Syndrome 
CBC 
 
Complete blood counts 
CI 
 
Confidence interval 
CH 
 
Heavy chain constant region 
CL 
 
Light chain constant region 
eCRF 
 
Electronic Case report form 
CRA 
 
Clinical Research Associate 
CRP 
 
C-reactive Protein 
CT 
 
Computed tomography 
CTCAE  
Common terminology criteria for adverse events 
CYP3A4  
Cytochrome P450, 3A4 subfamily 
DEXA 
 
Dual Energy X-Ray Absorptiometry 
EC 
 
Ethics Committee 
EKG 
 
Electrocardiogram 
EN 
 
Expected Sample Size 
ECOG 
 
Eastern Cooperative Oncology Group 
ELISA 
 
Enzyme-linked immunosorbent assay 
EORTC-QLQ 
European Organization for Research and Treatment of Cancer – Quality of Life 
Questionnaire 
GCP 
 
Good clinical practice 
GLP 
 
Good laboratory practice 
GMP 
 
Good manufacturing practice 
HIV 
 
Human immunodeficiency virus 
IgG 
 
Immunoglobulin G 
IL-1 α 
 
Interleukin-1 α 
IL-1β  
 
Interleukin-1 β 
IL-1 RA  
Interleukin-1 receptor antagonist 
IL-1R1 
 
Interleukin-1 Receptor 1 
IL-1R2 
 
Interleukin-1 Receptor 2 
INR  
 
International normalized ratio 
IRB 
 
Institutional review board 
irRC 
 
Immune Related Response Criteria 
LBM 
 
Lean Body Mass 
NF-κB   
Nuclear Factor kappa-light-chain-enhancer of activated B cells 
NSCLC  
Non-Small Cell Lung Cancer 
pI 
 
Isoelectric Point 
SAE 
 
Serious Adverse Event 
PK 
 
Pharmacokinetics 
PFS 
 
Progression Free Survival 
TNFα 
 
Tumor necrosis factor α 
TGFβ 
 
Transforming growth factor β 
TNF 
 
Tumor necrosis factor 
ULN 
 
Upper limit of normal 
WBRT 
 
Whole brain radiation therapy 
WOCBP  
Women of childbearing potential 
 


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1. BACKGROUND 
 
1.1 TARGETING INTERLEUKIN-1 ALPHA (IL-1α) 
 
Specific antagonism of IL-1α through Xilonix™ therapy is viewed as a unique, broad acting 
tumor suppression strategy that encompasses significant activity to ameliorate symptoms 
associated with the disease. IL-1α is unique in its involvement in so many processes related to 
tumor progression and collateral symptomatic effects of malignancy. The excellent safety and 
tolerability profile of the agent make it an ideal treatment option in advanced stage disease, 
particularly where the use of cytotoxic or other therapies with considerable toxicity are not 
supported by the risk benefit profile. 
 
 
Figure 1.1  
 
 
 
 
IL-1α is expressed constitutively on monocytes and platelets and may be expressed by 
tumors. IL-1α activity promotes tumor growth and spread through multiple pathways. 
 
In the setting of metastatic cancer, the loss of lean body mass is without doubt a prognostic factor 
for mortality, irrespective of underlying tumor type2,3,4,5. Multiple clinical investigations have 
shown that wasting predicts toxicity due to conventional chemotherapy, time to disease 
progression, and overall mortality in virtually all forms of cancer6,7,8,9,10. Loss of lean mass with 
advanced cancers thus represents a common final pathway amongst varied tumor types, which 
ultimately leads to death. 
 
Blocking IL-1α appears to normalize the metabolic energy balance with the net accumulation of 
lean body mass (LBM). An average LBM increase of 1.9±2kg was seen in 70% of patients treated 
(p<0.001) compared to their baseline values. These same patients had improvements in pain, 
anorexia, and fatigue as measured by the EORTC-QLQ-C30. For the first time, a non-toxic, anti-
neoplastic agent has shown evidence of the ability to reverse the devastating metabolic symptoms 
observed in advanced cancer patients. Even more impressive, however, was that increases in 
LBM also correlated with an increased overall survival. 
 
 


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1.2 PLEIOTROPIC MECHANISM OF ACTION 
 
There are over six-thousand published manuscripts on the science and physiology of IL-1α. The 
multitude of reports relate to the breadth and importance of this molecule in human physiology. 
Among these is its role in the growth, spread and collateral damage caused by tumors.  
 
Neutralizing IL-1α activity with a monoclonal antibody therapy is believed to have broad 
antineoplastic activity. Depending on the site of action, IL-1α mediates a number of crucial 
physiological processes related to response to injury (e.g. tumor growth). At the site of injury 
(such as in the microenvironment of the growing tumor), IL-1α induces the expression of 
vascular growth factors including vascular endothelial growth factor (VEGF), thereby mediating 
growth and angiogenesis11,12 (Figure 1.2). IL-1α also induces expression of matrix 
metalloproteinases that, in turn, have pleiotropic activities including tissue matrix breakdown, 
regulation of FAS mediated apoptosis and inflammation13,14. 
 
Through its role on platelets, IL-1α also regulates interactions between endothelial cells and 
leukocytes, driving activation of vascular endothelial cells and transendothelial migration of 
inflammatory cells into the tumor microenvironment15. Similarly, tumor-platelet microemboli 
formed between platelets and circulating tumor cells, provides tumor cells with enhanced ability 
to migrate from the vasculature into the tissues, forming new metastasis. Finally, IL-1α links 
these tumor processes to metabolic dysregulation, by signaling an injury response through IL-1 
receptors on POMC neurons that interdigitate the endothelial microvasculature of the 
hypothalamus. 
 
 
 


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Figure 1.2: IL-1α Mediates Tumor Growth 
 
 
 
Initial growth of tumor results in an irregular microvasculature leading to enhanced platelet 
interaction with vascular endothelial cells. IL-1α present on platelets and/or produced by 
tumor cells activates the endothelium, resulting in upregulation of adhesion molecules 
(ICAM, VCAM, E-selectin) and secretion of chemotactic cytokines (IL-8, MCP-1), 
facilitating 
diapedesis 
and 
recruitment 
of 
leukocytes 
into 
the 
tumor 
microenvironment16,17,18. IL-1α released from necrotic tissue and present on infiltrating 
tumor associated macrophages (TAMs) induce expression of MMPs, VEGF and other 
factors crucial to tumor survival, growth, and spread19,20,21,22. Additionally, TAMs suppress 
T-cell proliferation, allowing tumor cells to escape immune surveillance. 
 
Tumor cells travel with lymphatic drainage or penetrate the basement membrane to reach 
the circulation. In the circulation “sticky” tumor cells can interact with and adhere to 
platelets to form tumor-platelet micro-emboli. Inhibition of IL-1α signaling in the tumor 
microenvironment is thus expected to inhibit tumor growth by blocking IL-1α effects on 
tumor survival, neoangeogenesis and tissue matrix remodeling. 
 
 
 
 


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Figure 1.3: IL-1α Role in Hematogenous Spread and Metastasis 
 
 
 
Tumor-platelet aggregates or “microemboli” are formed by the adherence of tumor cells 
and platelets via membrane glycoprotein interactions23. By adhering platelets on their 
surface, tumor cells hijack the platelets ability to activate vascular endothelium. IL-1α 
present on the surface of platelets plays a role in activating vascular endothelium and 
facilitating transendothelial migration of tumors. Thus the platelet-IL-1α system provides 
a mechanism for invasion of circulating tumors into tissue to form new sites of 
metastasis24,25. Inhibition of IL-1α mediated platelet activation of the vascular endothelium 
is expected to reduce the potential for tumors to extravasate the blood vessel and penetrate 
into tissue. Therefore, reducing the metastatic potential of tumors. 
 
 
 


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Figure 1.4: Role for IL-1α in Metabolic Dysregulation 
 
 
 
Platelet-tumor microemboli interact with endothelial cells of microvasculature in the 
arcuate nucleus. IL-1α on the surface of microemboli can trigger IL-1 receptors on VE. 
However, fenestrations in the microvasculature of the hypothalamus are also penetrated by 
neuronal cells that express IL-1 receptor26. These cells, such as the POMC neurons, can 
respond to IL-1 stimulation to mediate central nervous system control of appetite, 
metabolism and well-being27,28,29. In times of acute stress (such as trauma or illness), these 
neurons are able to sense “danger” and drive physiological mechanisms that provide 
enhanced ability to respond to stress, including breakdown of muscle protein for the 
mobilization of amino acid substrates to provide for gluconeogenesis. When the “danger” 
signal is chronic, as it is in cancer, this process drives pathologic wasting, including loss 
of crucial cardiac and diaphragmatic muscle. Treatment with Xilonix™ is expected to 
reduce IL-1α mediated signaling at the level of the hypothalamus. This will enable the 
body to normalize metabolic activity and correct the underlying wasting phenotype 
associated with malignancy. 
 
1.3 REVIEW OF THE IL-1 SYSTEM 
 
Interleukin-1 alpha (IL-1α) is a 20kD protein expressed on the surface of a variety of cells either 
constitutively or after stimulation. Perhaps most importantly, IL-1α is constitutively found on 
peripheral blood cells, particularly platelets and monocytes, where it appears to play a crucial role 
in triggering and sustaining chronic inflammatory responses.  
 


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For a more detailed discussion, please see “Review of the IL-1 System” in the Investigator’s 
Brochure. 
 
1.4 OBSERVATION IN PREVIOUS STUDY: MABP1 INCREASED LEAN BODY MASS 
IN PATIENTS WITH REFRACTORY METASTATIC CANCER 
 
Anti-IL-1α therapy was used to treat patients at MD Anderson Cancer Center’s so-called Phase I 
treatment facility in Houston, Texas, which offers the latest in emerging experimental treatments. 
These were patients with refractory, metastatic disease that had failed a median of 5 regimens of 
previous therapy. Patients were defined as refractory since they had failed all standard of care 
therapy and had no remaining therapeutic options that would be expected to provide benefit.  
 
Of the 24 patients that were restaged according to RECIST criteria, an overall response rate of 
37% (9/24) was achieved (defined as stable disease or better for ≥ 3 months). 10 NSCLC patients 
were restaged using the immune related response criteria (irRC), and a 20% (2/10) response rate 
was observed. Out of these 34, 30 patients complied as scheduled with DEXA scans both at 
screening and at the 8-week follow-up assessment.  
 
Analysis of baseline and follow-up DEXA scans showed the remarkable finding that most 
patients, 70% (21/30), had objective increases in lean body mass (LBM). Responders showed an 
average LBM improvement of 1.9±2.0 kg (p<0.001) compared to their baseline values, while the 
average change for the entire cohort was 1.0 kg (p=0.02) 
 
 
Figure 1.5 
 
 
 
 
Most patients (21/30 or 70%) showed increase in lean body mass (LBM) of 1.9±2.0 kg 
after three infusions of antibody therapy (p<0.001). Patients were evaluated with DEXA 
no more than 2 weeks prior to the start of treatment. Each bar represents the change in 
LBM for a single patient. Lean body mass change is expressed as a percentage of total 
body weight from baseline.  
 
-8%
-3%
2%
7%
12%
17%
1 2 3 4 5 6 7 8 9 101112131415161718192021222324252627282930
Change in LBM (%)


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In the current study, most patients that entered study had dramatic loss in body weight prior to 
enrollment, which is presumed to have been primarily muscle mass (See Figure 1.6). A reversal 
of this muscle wasting is not known to occur in patients with refractory metastatic disease. To our 
knowledge, there are no reports in the literature of an agent able to facilitate increases in LBM at 
this stage of disease.  
 
Regulation of energy balance is known to be orchestrated by the central nervous system (CNS), 
via the hypothalamic-pituitary-adrenal axis (HPA). Since IL-1 signaling is known to trigger 
cachexia via signaling at the hypothalamus, these results point to a correction of the IL-1-driven 
inflammatory signaling at the hypothalamus. 
 
 
Figure 1.6 
 
  
 
Each line represents the trajectory of body weight for each patient. Patient body weights at 
least 6 months prior to screening for the current study are represented as 100%, and 
compared to that measured during the study screening/enrollment process. The steep 
negative slope shows that the large majority (23/30, 77%) of patients were experiencing 
significant body weight loss upon entry into the study. Prior body weights were obtained 
from medical records. 
 
The results reported here are particularly remarkable. First, these results provide the most 
substantive evidence to date that an anti-inflammatory therapy can target the malignant 
inflammation that drives muscle catabolism in patients with cancer-associated cachexia. This 
result was also obtained in an advanced, heavily pre-treated (median=5 previous 
chemotherapeutic regimens) cancer population who had lost a mean of 5% of their body weight 
in the previous 6 months before entering the trial. Finally, the drug was well tolerated with few 
possibly drug related AEs, no infusion reactions, and only one possibly drug related SAE (lung 
-27%
-22%
-17%
-12%
-7%
-2%
3%
8%
Pre-screen
Screening
Weight change (%) before screening
Losing
Weight
Gaining
Weight


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infection in patient with disseminated NSCLC). Treatment with Xilonix™ is thus expected to 
provide a safe and effective treatment option to treat refractory cancer patients. 
 
1.5 ANALYSIS OF COLORECTAL COHORT 
 
A large proportion of patients enrolled and treated in this pilot trial had refractory metastatic 
colorectal cancer (14 out of 52). Five of these CRC patients responded with an increase in LBM, 
and the average increase was 4.6%.   
 
Among the 14 subjects with colorectal carcinoma, the median overall survival was 6.7 months for 
the intent to treat population (which included three patients enrolled with waivers) and 8.7 
months for the per-protocol population.  
 
Median survival duration correlated strongly with increases in LBM. For those with an objective 
evidence of an increase in LBM from baseline to week 8, the median survival duration was 19.3 
months. This is in sharp contrast to a median OS of 6.6 months seen in those with no evidence of 
LBM increase. While the single arm design of the trial does not enable us to conclude that the 
increased survival was the result of drug effect, it does strongly suggest that an increase in LBM 
in this advanced population will correlate favorably with survival. 
 
Subjects enrolled in this trial were also evaluated for tumor response using RECIST 1.1. As a 
result, subjects were discontinued due to radiographic evidence of disease progression. This 
resulted in the discontinuation of some patients who were potentially experiencing clinical benefit 
in the form of increased LBM. Had these subjects been allowed to continue on study and further 
receive drug it might be expected that these responses would have translated into even more 
significant clinical and survival benefit. 
 
 
Figure 1.7 
 
 


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Kaplan–Meier curve showing survival among colorectal cancer patients (n=14) according 
to evidence of LBM increase. 5 of 14 (36%) responded with an increase in LBM after just 
8 weeks (3 infusions). Those with LBM increase had a median OS of 19.3 months vs 6.6 
months in those who lost LBM. 
 
1.6 QUALITY OF LIFE ANALYSIS 
 
Quality of life (QoL) was assessed using the EORTC QLQ-C30 questionnaire. QoL assessments 
were performed at baseline and prior to follow up DEXA scans. This information was available 
for 33 patients. Several domains of this instrument showed improvement in this patient 
population--including social, emotional, and role functions. At the same time, a robust decrease in 
the symptoms of fatigue, pain, and appetite loss were observed. The absolute score point 
reductions were 11.1 (p=0.008), 11.1 (p=0.025), and 12.5 (p=0.02), respectively. And finally, an 
improvement in Global QoL was achieved, and this result was statistically significant (p=0.02). 
These findings are summarized in figure 1.8. 
 
 
Figure 1.8 
 
 
 
Change in quality of life as assessed by EORTC QLQ-30 questionnaire. Emotional, Social, 
and Role functions improved significantly at week 8 showing an average increase of 
6.1±15 (p=0.032), 9.1±24 (p=0.042), and 12.1±23 (p=0.006) respectively. Substantial 
reduction on fatigue (-11±22, p=0.008), pain (-11±27, p=0.025), and appetite loss (-
12.5±29, p=0.02) was observed during this period. The Global QoL increased from 4.8 to 
5.4 (0.6 score points, p=0.02). 
  
1.7 CORRELATIVE ANALYSIS 
 
Analysis of serum cytokine levels has shown a reduction in IL-6 levels after treatment with 
Xilonix™. Of the 52 subjects, 43 had data available from screening and at week 8. One subject 
with Castleman’s disease, however, was not included in the analysis as their serum levels were 
150 times greater than the cohort average. The mean serum IL-6 levels for these 42 subjects was 
20.8±23.4 (median 12.8) pg/ml, which decreased to a mean of 15.9±27.1 (median 7.6; p=0.08) 
after 8 weeks of treatment. This decrease was even more pronounced when stratified by LBM 
response. IL-6 levels for subjects who increased LBM (N=20) changed from an average of 
16.5±12.5 (median of 12.3) to an average of 10.9±12.9 (median of 6.2 pg/ml; p=0.044). Those 


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subjects who did not respond had non-statistically significant increases in IL-6 levels. Figure 1.9 
details these responses. 
 
 
Figure 1.9 
 
 
Plasma IL-6 levels were measured by ELISA. Overall for the entire patient population, 
plasma IL-6 levels declined. However, stratification of the data among patients that had 
increases in LBM versus those that lost LBM revealed differences. LBM increase was 
associated with declining serum IL-6 at week 8, while patients with LBM loss did not show 
reduction in plasma IL-6 levels (Overall population (n=43): Average change -4.9±26 
(median -2.7) pg/ml, p=0.08; Responders (n=20): Average change -5.6±13 (median -3.2) 
pg/ml, p=0.044; Non- responders (n=6): Average change -3.8±21 (median -0.4) pg/ml, p= 
0.91). 
 
IL-1α is expressed on the surface of platelets, thus platelet numbers were analyzed across dose 
cohorts. Increases in platelet counts are known to occur in many advanced cancer patients, and 
can be a prognosticator of disease progression30. In this trial, platelet counts appeared to increase 
over time (Figure 1.10), however, there also appeared to be dose dependent abrogation of platelet 
compartment expansion. This is the likely result of decreasing serum IL-6 levels, as there was no 
evidence of platelet destruction in these patients. 
 
 
 


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Figure 1.10 
 
 
Platelet counts were determined as part of routine blood analysis. Platelet numbers showed 
a trend of increasing over time in advanced cancer patients and can be a prognosticator 
disease progression. Platelet counts presented are differences between those measured prior 
to treatment and at week 8 (after three rounds) of antibody therapy. The 3.75mg/kg dose 
cohort was initially provided every three weeks. This dosing was increased in frequency to 
every two weeks (2 week).  
 
Flow cytometry was also used to examine IL-1α expression on CD14+CD16+ monocytes. 
Treatment with Xilonix™ resulted in a trend of reducing IL-1α+CD14+CD16+ monocytes (as a 
percentage of CD14+CD16+). This reduction was observed without an overall decrease in the 
absolute number of monocytes, which suggests Xilonix™ binding to IL-1α on the surface of 
these potentially pathogenic cells. Decreases in IL-1α+CD14+CD16+ monocytes appeared to 
rebound towards the end of dosing cycles (Figure 1.11). 
 
 
 
 


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Figure 1.11 
 
 
 
Chart shows IL-1α expressing monocytes present in peripheral blood as percentage of 
CD14+CD16+ monocytes. Blood samples were analyzed from patients at screening, prior 
to infusion with Xilonix™, until cycle 5, day one post infusion (C2D15). The n values 
change over time, as patients are lost from study. Trend appears to show treatment 
reduction in exposed IL-1α present on this monocyte subset. 
 
 
 
35
45
55
65
Screening
(n=33)
C1D1
(n=31)
C1D8
(n=31)
C1D15
(n=21)
C2D1
(n=24)
C2D8
(n=21)
C2D15
(n=14)
IL-1a %


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2. INVESTIGATIONAL PRODUCT 
 
2.1 ACTIVE INGREDIENT, PHARMACOLOGIC CLASS, STRUCTURE 
 
The active ingredient in the drug product Xilonix™ is MABp1, a recombinant human IgG1 
monoclonal antibody specific for human interleukin-1α (IL-1α). The entire MABp1 heavy and 
light chain sequences are identical to those found in naturally-occurring human IgG1κ, with the 
light and heavy chain variable regions being identical to those originally expressed by a 
peripheral blood B lymphocyte that was obtained from a healthy individual. 
 
 
Figure 2.1: MABp1 Antibody 
 
 
 
 
The MABp1 primary glycoform has a molecular weight of 148.1 kilodaltons. Like all IgG1 
molecules, the heavy chains are joined at their hinge regions through two disulfide linkages, and 
each heavy chain is joined to one light chain through one disulfide linkage between their CH1 and 
CL domains respectively. 
 
The main isoform has a pI of about 9.2 and comprises about 70-80% of the total isoform 
population in all lots that have been manufactured to date, as determined by capillary isoelectric 
focusing. The heavy chain CH2 domains are glycosylated primarily with the oligosaccharide 
structure shown in Figure 2.1, as determined by mass spectroscopy of the cleaved glycans. The 
glycosylated residue (Asn-302 as numbered from the N-terminus of MABp1) has been 
determined by peptide mapping to be in the same highly conserved N-linked glycosylation site as 
found in endogenous IgG1 (Asn-297 according to the generic numbering system). Similarly, the 
primary glycan, commonly referred to as G0F, is the same as that found on about 22% of 
endogenous human IgG molecules31.  
 
The entire MABp1 heavy and light chain sequences are identical to those found in naturally-
occurring human IgG1κ, with the light and heavy chain variable regions being identical to those 
originally expressed by a peripheral blood B lymphocyte that was obtained from a healthy 
individual.   
 
Endogenous anti-IL-1α antibody has been reported in 5% to 28% of healthy serum or plasma 
samples32,33. It has been measured in cord blood, children and adults34. The anti-IL-1α antibodies 


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measured in human plasma have been strictly of the IgG class, particularly IgG1, IgG2, and IgG4. 
Relatively equal distribution is seen in male and female plasma35. Binding affinities reported for 
endogenous anti-IL-1α antibodies, ranging from 4 to 16 pM, are comparable to that for MABp1, 
the specification for which is 22 to 260 pM. 
  
It is important to point out that affinity maturation had already taken place in the human host, and 
therefore no in vitro affinity maturation was required to increase the natural binding affinity of 
MABp1. Also important is the fact that, unlike most other therapeutic IgG products, for which the 
Fc regions are derived from a rare human allele, XBiotech’s product includes a heavy chain in 
which the constant (CH) region represents an allele found in approximately 70% of the human 
population. These two features should make for a drug product with reduced potential for 
immunogenicity. 
 
2.2 DRUG PRODUCT (XILONIX™) DESCRIPTION 
 
XBiotech’s proposed drug product, Xilonix™, is a sterile injectable liquid formulation of 50 
mg/mL MABp1 in a stabilizing isotonic buffer (pH 6.4). Each 10-mL serum vial contains 6 mL 
of the formulation, and is sealed with a 20-mm grey bromobutyl stopper and flip-off aluminum 
seal. Product should be stored at 2-8°C in the dark, with excursions to room temperature 
permitted in order to prepare the drug product for use. The exact composition of the drug product 
is shown below:   
 
Composition of the Final Drug Product 
Ingredient 
Grade 
Manufacturer 
Concentration 
MABp1 antibody 
GMP 
XBiotech 
50 mg/mL 
sodium phosphate dibasic 
compendial 
JT Baker 
12 mg/mL 
citric acid monohydrate 
compendial 
JT Baker 
2 mg/mL 
Trehalose•2H2O (high-purity low endotoxin) 
compendial 
Ferro- Pfanstiehl 
60 mg/mL 
polysorbate 80 
compendial 
JT Baker 
0.2 mg/mL 
Phosphoric acid, to adjust pH 
compendial 
JT Baker 
0.04 mg/mL 
water for injection 
compendial 
Irvine Scientific 
(USA) 
- - 
 
2.3 DESCRIPTION AND COMPOSITION OF PLACEBO PRODUCT 
 
The placebo product is manufactured following the same procedures and batch records used to 
manufacture the MABp1 drug product. The placebo dosage form is a sterile isotonic formulation 
buffer at pH 6.2-6.5. Each 10-mL Type I borosilicate glass serum vial contains 6mL of the 
formulation buffer, and is sealed with a 20-mm Daikyo Flurotec butyl rubber stopper and flip-off 
aluminum seal. The product should be stored upright at 2-8°C in the dark, with excursions to 
room temperature permitted in order to prepare the drug product for use. The exact composition 
of the Placebo Product is shown in the table below: 
 
 
 
 
 
 
 
 


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2.4 STORAGE 
 
The recommended storage condition is upright in the dark, at 2-8°C. 
   
2.5 STABILITY 
 
The drug product is formulated in a buffer in which most of the tonicity comes from trehalose 
rather than salt. Trehalose is an effective stabilizer against oxidation, aggregation, thermal, and 
mechanical stress. Citrate was selected as the buffering agent due to its antioxidant properties. 
Extensive stability data indicates that the drug product is very stable, even under thermally and 
mechanically stressed conditions. Short excursions to room temperature have shown no negative 
effect on the product. However, the study treatment products are not to be frozen at any time. The 
drug product has been shown to be stable for up to 24 hours at room temperature after dilution in 
100 ml of normal saline, although it is recommended to store at 2-8°C after dilution whenever 
feasible.  The study treatment products are currently labeled with a 12-month retest date. 
 
2.6 METHOD OF ADMINISTRATION 
 
IV Administration  
 
Xilonix™ should be diluted in a 100-mL bag of normal saline prior to infusion. The following 
calculations must be used to determine the volume of drug product to be diluted for each study 
subject: 
 
50 mg/ml drug product, 7.5 mg/kg dose: 
  
Volume of drug product to be diluted = Vd = (Body Weight X Dosage) 
       
 
 
 
 
 
 
50 mg/mL 
 
(Body Weight should be rounded to the nearest whole number) 
 
Example for 70 kg Subject at 7.5 mg/kg: Vd = (70 kg X 7.5 mg/kg)  
                                                                                         50 mg/mL 
 
Vd = 10.5 mL (round to one decimal place) 
 
The calculated volume (Vd) should be withdrawn from the subject’s assigned vial(s) using a 
suitable syringe. The same amount of saline as the calculated drug should be removed from the 
100-ml bag. The calculated volume is then injected into the 100-mL IV bag of normal saline 
Composition of Placebo Product 
Ingredient 
Grade 
Manufacturer 
Concentration 
trehalose dihydrate 
compendial 
Ferro-Pfanstiehl 
(USA) 
60 mg/mL 
sodium phosphate dibasic 
compendial 
JT Baker (USA) 
12 mg/mL 
citric acid monohydrate 
compendial 
JT Baker (USA) 
2 mg/mL 
Polysorbate 80 
compendial 
JT Baker (USA) 
0.2 mg/mL 
Phosphoric acid, to adjust pH 
compendial 
JT Baker 
0.04 mg/mL 
water for injection 
compendial 
Irvine Scientific 
(USA) 
q.s. 


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(0.9% NaCl), resulting in a final total volume of 100 ml. The drug product should then be mixed 
by gently inverting the bag ten times.  
 
After priming the infusion set lines, the delivery pump should be programmed to deliver 100 mL 
of the diluted drug product over a 1-hour period (60 ± 15 minutes), with the subject being 
monitored for signs of an infusion reaction. The infusion should be chased with a minimum of 
30 mL of normal saline to deliver any product that may be held up in the dead volume of the 
infusion set. 
 
IMPORTANT:   
 
(1) The actual body weight of the subject on Cycle 1 Day 1, rounded to the 
nearest whole number, must be used in calculating their individual 
dosage. The same dosage calculated at C1D1 will be administered at 
each cycle visit following C1D1.  
 
(2) Some subjects may require more than one vial for a single infusion, 
depending on their body weight. 
 
(3) The diluted product must be administered the same day that it is diluted. 
 
2.7 AGENT ORDERING 
 
The Responsible Investigational Pharmacy will order study drug (Xilonix™ or placebo) from 
XBiotech as needed. 
 
2.8 POTENTIAL DRUG INTERACTIONS 
 
There are no known drug interactions with MABp1. In controlled trials that combined the use of 
IL-1ra with TNF inhibitors, a higher incidence of serious infection was noted. MABp1 has not 
been administered concomitantly with these agents in clinical trials. However, due to potential 
risk, it is not recommended that MABp1 be used in combination with anti-TNF agents.   
 
There are significant number of platelets and peripheral blood mononuclear cells that may be 
targeted by MABp1. Thus, there is the potential for MABp1 to cause thrombocytopenia, 
monocytopenia or neutropenia. However, to date, there has been no evidence that MABp1 can 
cause cytopenia of any kind.   
 
2.9 PROHIBITED AND RESTRICTED THERAPIES 
 
The following concomitant therapies are prohibited while on trial: 
 
• 
Therapeutic agents and biologics that target the IL-1 or TNF-alpha system 
• 
Live virus vaccines  
• 
Investigational agents 
Any radiation and/or chemotherapyNote: Concomitant palliative 
radiotherapy is allowed only if index lesions, and measurable new lesions, as 
defined by the immune related response criteria, are not included within the 
radiation field 
 
 


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3. STUDY DESIGN AND OBJECTIVES 
 
This is a phase III, double blind, placebo controlled, randomized, pivotal trial of the True Human 
monoclonal antibody MABp1 in subjects with refractory, metastatic colorectal cancer.  
 
Enrolled subjects will be randomized to receive either MABp1 plus best supportive care (BSC) or 
placebo plus BSC. BSC is defined as those measures intended to provide palliation of symptoms 
and improve quality of life. This includes, but is not limited to, antibiotics, anti-emetics, 
narcotics, and parenteral nutrition. 
 
The study will compare the overall survival (OS) between the MABp1 treated and placebo arms. 
Secondary endpoints will include change in lean body mass from screening to the cycle 5 
assessment and change in quality of life. Other secondary endpoints will be progression-free 
survival, response rate, disease control rate, and stabilization of platelet counts. LBM will be 
assessed through the use of dual-energy X-ray absorptiometry (DEXA) scans. Quality of life will 
be assessed with the EORTC QLQ-C30 (v.3). Response and progression will be evaluated using 
the Immune Related Response Criteria (irRC). 
 
Study Objectives: 
 
Primary Efficacy Endpoint 
 
• 
Overall survival (OS) will be the primary endpoint of this study, which will be measured 
from the date of randomization until death or last follow-up.  
 
Secondary Efficacy Endpoints 
 
• 
Secondary efficacy variables will include change in lean body mass (LBM) measured by 
dual-energy X-ray absorptiometry (DEXA) scans, change in Quality of Life assessed 
through the cancer-specific EORTC QLQ-C30 questionnaire, stabilization of platelet 
counts, progression free survival (PFS), objective response rate (ORR) and disease 
control rate (DCR).  


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4. ELIGIBILITY CRITERIA 
No waivers/exemptions will be granted for protocol inclusion/exclusion criteria. 
 
4.1 INCLUSION CRITERIA 
 
Subjects may be included in the study if they meet all of the following criteria: 
 
1. Subjects with pathologically confirmed colorectal carcinoma that is metastatic or 
unresectable and which is refractory to standard therapy. To be considered refractory, a 
subject must have experienced progression (or intolerance) after treatment with all of the 
following agents: oxaliplatin, irinotecan flouropyrimidine, and cetuximab or 
panitumumab if KRAS wildtype.    
2. Subjects will not be treated with any radiation, chemotherapy, or investigational agents 
while enrolled in this protocol.   
3. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2. 
4. At least 2 weeks since the last previous cancer treatment including:  chemotherapy, 
radiation therapy, immunotherapy, surgery, hormonal therapy, or targeted biologics and 4 
weeks for patients who received treatment immediately prior to the study with anti-IL-1 or 
anti-TNF agents. 
5. Age ≥ 18 years, male or female subjects. 
6. Serum potassium and magnesium levels within institutional normal limits. Total serum 
calcium or ionized calcium level must be greater than or equal to the lower limit of 
normal. Subjects with low potassium, calcium and magnesium levels may be replenished 
to allow for protocol entry. 
7. Adequate renal function, defined by serum creatinine ≤ 1.5 x ULN. 
8. Adequate hepatic function defined as:  
• 
total bilirubin ≤ 1.5 times the institutional upper limit ULN. 
• 
alanine aminotransferase (ALT) ≤ 2.0 times the institutional ULN. 
•  
• 
Exception: subjects with known liver metastases: ≤ 3.0 times the institutional 
ULN for ALT.  
9. Adequate bone marrow function as defined as: 
• 
absolute neutrophil count (neutrophil and bands) of ≥ 1,500/mm3 (≥ 1.5 x 109/L) 
• 
platelet count of ≥ 100,000/mm3 (≥ 100 x109/L) 
• 
hemoglobin of ≥ 9 g/dL 
10. For women of childbearing potential (WOCBP), a negative serum pregnancy test result at 
Screening and monthly thereafter.  
For women who are not postmenopausal (24 months of amenorrhea) or surgically sterile 
(absence of ovaries and/or uterus): agreement to use adequate methods of contraception, 
during the treatment period and for at least 1 month after the last dose of study drug.  
Acceptable contraceptive measures include: 
- 
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 hormone-
releasing system(IUS) 


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- 
Barrier or sterilization methods such as condoms, bilateral tubal occlusion, 
vasectomized partner or sexual abstinence  
For men: agreement to use a barrier method of contraception during the treatment period 
and for at least 1 month after the last dose of study drug  
 
11. Signed and dated institutional review board (IRB)-approved informed consent before any 
protocol-specific screening procedures are performed. 
12. Patients enrolled must, in the Investigator’s judgment, be healthy enough to stay on the 
clinical trial for three months. 
 
4.2 EXCLUSION CRITERIA 
 
Subjects will be excluded from the study if they meet any of the following criteria: 
 
1. Mechanical obstruction that would prevent a patient from receiving adequate nutritional 
intake. 
2. A serious uncontrolled medical disorder or active infection that would impair the ability 
of the patient to receive protocol therapy.  
3. Uncontrolled or significant cardiovascular disease, including:  
• 
A myocardial infarction within 6 months 
• 
Uncontrolled angina within 3 months  
• 
Congestive heart failure within 3 months defined as NYHC-II  
• 
Diagnosed or suspected congenital long QT syndrome  
• 
Any history of clinically significant ventricular arrhythmias (such as ventricular 
tachycardia, ventricular fibrillation, Wolff-Parkinson-White (WPW) syndrome, 
or torsade de pointes). Prolonged QTc interval on pre-entry electrocardiogram 
(>450 msec). If the automated reading is prolonged (i.e., >450 msec), the EKG 
should be manually over-read.  
• 
Any history of second or third degree heart block (may be eligible if currently 
have a pacemaker)  
• 
Heart rate <50 beats per minute on pre-entry electrocardiogram  
• 
Uncontrolled hypertension (blood pressure >140 mm Hg systolic and >90 mm 
Hg diastolic).  
4. Dementia or altered mental status that would prohibit the understanding or rendering of 
informed consent. 
5. Subjects who have not recovered from the adverse effects of prior therapy at the time of 
enrollment to ≤ grade 1; excluding alopecia and grade 2 neuropathy. 
6. Immunocompromised subjects, including subjects known to be infected with human 
immunodeficiency virus (HIV). 
7. Known hepatitis B surface antigen and/or positive hepatitis C antibody and presence of 
hepatitis C RNA. 
8. History of tuberculosis (latent or active) or known positive Interferon-gamma release 
assay (IGRA). 
9. Receipt of a live (attenuated) vaccine within 1 month prior to screening. 
10. Subjects with history of hypersensitivity to compounds of similar chemical or biologic 
composition to Xilonix™. 
11. Women who are pregnant or breastfeeding. 


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12. WOCBP or men whose sexual partners are WOCBP who are unwilling or unable to use 
an acceptable method of contraception for at least 1 month prior to study entry, for the 
duration of the study, and for at least 1 month after the last dose of study medication. 
13. Weight loss >20% in the previous 6 months. 
14. History of progressive multifocal leukoencephalopathy or other demyelinating disease 
15. Subjects on immunosuppressive therapy, including transplant patients 
 


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5. TREATMENT PLAN 
 
This is a phase III, multicenter, double blind, randomized, placebo controlled pivotal trial of the 
True Human monoclonal antibody MABp1 in subjects with metastatic colorectal cancer who are 
refractory to standard therapy. 
 
• 
Enrolled subjects will be randomized (2:1) to receive either MABp1 plus best supportive 
care (BSC) versus placebo plus BSC. 
• 
BSC is defined as those measures intended to provide palliation of symptoms and 
improve quality of life. This includes, but is not limited to, antibiotics, anti-emetics, 
narcotics, and parenteral nutrition. 
• 
Subjects randomized to MABp1 or placebo will receive 7.5 mg/kg of study drug via 
intravenous infusion once every 2 weeks (one cycle).  
• 
Study drug will be administered under close observation in a facility equipped to handle 
medical emergencies. Subjects must be observed for at least 1 hour with stable vital signs 
following the end of the infusion.   
• 
Efficacy will be assessed by measuring the difference in median overall survival (OS) 
between the MABp1 and placebo groups.   
• 
Secondary endpoints will include change in lean body mass (LBM) from baseline to 
cycle 5, change in Quality of Life, stabilization of platelet counts, progression free 
survival (PFS), objective response rate (ORR) and disease control rate (DCR). Lean body 
mass measurements will be obtained through the use of dual-energy X-ray 
absorptiometry (DEXA) scans. Quality of life will be assessed with the EORTC QLQ-
C30 (v. 3). Response and progression will be evaluated using the Immune Related 
Response Criteria (irRC). 
• 
Safety assessments will include physical examinations, vital signs, standard clinical 
laboratory evaluations (blood chemistry, urinalysis, and hematology), allergic reaction 
monitoring and adverse event monitoring.  
• 
Pharmacokinetics samples will be taken in all patients. The pharmacokinetics of MABp1 
in plasma will be randomly analyzed. Plasma samples will also be randomly monitored 
for the development of anti-MABp1 antibodies.  If the study meets the primary endpoint, 
then all samples will be tested. 
 
5.1 DOSE MODIFICATIONS 
 
Subjects will be monitored continuously for adverse events (AEs) while on study therapy. 
Subjects will be instructed to notify their physician immediately for any and all AEs. Adverse 
events will be graded according to CTCAE version 4.0. Dose modifications will be made for:  
 
a) Subjects who experience an adverse event of grade 3 or greater that is probably related to the 
study drug will be withdrawn from study and will be followed until the resolution of toxicity. 
 
b) Subjects who experience an adverse event of grade 3 or greater that is possibly related to the 
study drug will not be retreated with subsequent cycles until the adverse event resolves to grade 1 
or less. Subjects who require greater than 14 days of treatment delay due to toxicity that is 
possibly related to the study drug will be removed from the study and followed until resolution of 
toxicity.  
 
 


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5.2 DISCONTINUATION OF THERAPY 
 
Study therapy MUST immediately be discontinued for any the following reasons:  
 
• 
Radiographic evidence of tumor progression as defined by the Immune Related Response 
Criteria (see section 7.5) 
• 
Withdrawal of informed consent (subject’s decision to withdraw for any reason)  
• 
Any clinical adverse event, laboratory abnormality, inter-current illness, or progression of 
disease which, in the opinion of the Principal Investigator, indicates that continued 
participation in the study is not in the best interest of the subject 
• 
Pregnancy  
• 
Termination of the study by the sponsor 
• 
Imprisonment or the compulsory detention for treatment of either a psychiatric or 
physical (e.g., infectious disease) illness  
• 
Subjects will also be discontinued based on 5.1a. 
 
5.3  EMERGENCY UNBLINDING 
Subjects and Investigators will be unblinded as to treatment allocation after all patients have 
completed the study and the database is locked (routine unblinding).  In the event of an 
emergency that would require the investigator to be aware of the treatment allocation prior to the 
end of the trial, the investigator can obtain this information, on a per Patient basis, from the 
Sponsor’s electronic database at the Investigative site. The investigator is not required to contact 
the sponsor or sponsors representative prior to unblinding, but is encouraged to do so if there are 
any questions regarding the unblinding procedure or need to unblind. 
Examples of events that would qualify as emergent are as follows: 
 
 
A grade 3 or greater AE which are “probably or definitely” related to study drug 
administration, such as a grade 3 infusion reaction, and where treatment assignment 
information is essential for the management of the event.  Per section 5.1 (a), this type of 
reaction would require that the patient receives no further doses, and is followed until the 
resolution of the toxicity. 
 
Any suspected, unexpected, serious adverse reaction (SUSAR) 
 
Pregnancy  
 
 
 
 
 
 
 
 
 


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5.4 STUDY PROCEDURES 
 
Screening-14 days are allowed to complete all procedures and the first dose (C1D1) must occur 
within 7 days of randomization: 
 
• 
Informed Consent  
• 
Medical History 
• 
Physical Exam 
• 
Height 
• 
Weight 
• 
Vital Signs 
• 
ECOG Evaluation  
• 
Hematology panel: CBC with differential and platelets  
• 
Chemistry panel  
• 
PT/aPTT/INR 
• 
Urinalysis 
• 
Serum Pregnancy 
• 
C-Reactive Protein  
• 
EORTC QLQ-C30 
• 
Prior Medications  
• 
TNM staging 
• 
Randomization- after confirmation that subject meets all inclusion/exclusion criteria 
• 
DEXA Scan- Lean Body Mass/Body Composition 
• 
Tumor Measurements- Assessments can include CT or MRI, and whichever modality is 
chosen for the initial tumor assessment must be used for the week 8 assessment. The 
choice of modality should be based primarily on the type of scan that the patient has 
previously received as their standard of care. Standard of care scans obtained within 28 
days prior to C1D1 may be used as screening scans. 
 
DEXA scans should be scheduled to occur prior to CT or MRI tumor measurements. In the 
event that these scans are obtained prior to the DEXA scan (such as scans done for standard of 
care), then there must be a 10 day washout prior to obtaining the DEXA scan. 
 


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Note:  These schema show the maximum window sizes for completion of the radiologic 
procedures.  The key elements are: 
• 
Baseline tumor assessment should be done within 28 days of C1 D1 
• 
A 10 day washout period is required for DEXA scans acquired after a CT 
• 
Alternatively, the DEXA scan can be obtained prior to tumor measurements 
PT023: Screening and Randomization 
Options pertaining to CT Availability 
 
A. CT Available Before Screening (within 28 days of dosing) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
B. CT Unavailable Before Screening 
 
 
*CT with Contrast (standard of care) performed within 28 days prior to 
treatment on study may be used as the Baseline Scan. 
**DEXA should be completed no earlier than 10 days after CT with Contrast 
(standard care). 


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Cycle 1 Day 1 (C1D1): 
 
• 
Physical Exam 
• 
Weight 
• 
Vital Signs (pre-infusion) 
• 
ECOG Evaluation 
• 
Hematology panel: CBC with differential, platelets (pre-infusion) 
• 
Chemistry panel (pre-infusion) 
*Urinalysis, Hematology and Chemistry panels that are obtained for the purpose of screening 
a subject, and that are drawn within 72 hours of C1D1, may also be used for the C1D1 
baseline safety lab values. 
• 
Urinalysis (pre-infusion) 
• 
CRP (pre-infusion) 
• 
PK Sampling (pre-infusion) 
• 
Study Drug infusion 
• 
Vital signs (60 minutes post-infusion) 
• 
PK Sampling (30-90 minutes post-infusion) 
• 
Adverse Event monitoring 
• 
Concomitant Medications 
 
Cycle 2 Day 1 +/- 2 days (C2D1): 
 
• 
Physical Exam 
• 
Weight 
• 
Vital Signs (pre-infusion) 
• 
ECOG Evaluation 
• 
Hematology panel: CBC with differential, platelets (pre-infusion) 
• 
Chemistry panel and serum pregnancy (pre-infusion same tube) 
• 
Urinalysis (pre-infusion) 
• 
CRP (pre-infusion) 
• 
PK Sampling (pre-infusion) 
• 
Study Drug infusion 
• 
Vital signs (60 minutes post-infusion) 
• 
PK Sampling (30-90 minutes post-infusion) 
• 
Adverse Event monitoring 
• 
Concomitant Medications 
 
Cycle 3 Day 1 +/- 2 days (C3D1): 
 
• 
Physical Exam 
• 
Weight 
• 
Vital Signs (pre-infusion) 
• 
ECOG Evaluation 
• 
Hematology panel: CBC with differential, platelets (pre-infusion) 
• 
Chemistry panel (pre-infusion) 
• 
Urinalysis (pre-infusion) 
• 
CRP (pre-infusion) 
• 
PK Sampling (pre-infusion) 


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• 
Study Drug infusion 
• 
Vital signs (60 minutes post-infusion) 
• 
PK Sampling (30-90 minutes post-infusion) 
• 
Adverse Event monitoring 
• 
Concomitant Medications 
 
Cycle 4 Day 1 +/- 2 days (C4D1): 
 
• 
Physical Exam 
• 
Weight 
• 
Vital Signs (pre-infusion) 
• 
ECOG Evaluation 
• 
Hematology panel: CBC with differential, platelets (pre-infusion) 
• 
Chemistry panel and serum pregnancy (pre-infusion same tube) 
• 
Urinalysis (pre-infusion) 
• 
CRP (pre-infusion) 
• 
PK Sampling (pre-infusion) 
• 
Study Drug infusion 
• 
Vital signs (60 minutes post-infusion) 
• 
PK Sampling (30-90 minutes post-infusion) 
• 
Adverse Event monitoring 
• 
Concomitant Medications 
 
Cycle 5 Day 1 +/- 2 days (C5D1): 
 
• 
Physical Exam 
• 
Weight 
• 
Vital Signs (pre-infusion) 
• 
ECOG Evaluation 
• 
Hematology panel: CBC with differential, platelets (pre-infusion) 
• 
Chemistry panel (pre-infusion) 
• 
Urinalysis (pre-infusion) 
• 
CRP (pre-infusion) 
• 
PK Sampling (pre-infusion) 
• 
Study Drug infusion 
• 
Vital signs (60 minutes post-infusion) 
• 
PK Sampling (30-90 minutes post-infusion) 
• 
Adverse Event monitoring 
• 
Concomitant Medications 
• 
EORTC QLQ-C30 
• 
DEXA scan for lean body mass/body composition (+/- 3 days of C5D1) 
• 
Tumor Measurements (+/- 3 days of C5D1- AFTER DEXA SCAN) 
 
Cycle 6+- Follow up visits will occur every 14 days (+/- 2 days) for all subjects who remain on 
trial:  
 
• 
Physical Exam 
• 
Weight 


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• 
Vital Signs (pre-infusion) 
• 
ECOG Evaluation 
• 
Hematology panel: CBC with differential, platelets (pre-infusion) 
• 
Chemistry panel and serum pregnancy (pre-infusion same tube). Serum pregnancy to be 
completed every 2 cycles.  
• 
Urinalysis (pre-infusion) 
• 
CRP (pre-infusion) 
• 
PK Sampling (pre-infusion) 
• 
Study Drug infusion 
• 
Vital signs (60 minutes post-infusion) 
• 
PK Sampling (30-90 minutes post-infusion) 
• 
Adverse Event monitoring 
• 
Concomitant Medications 
• 
Tumor Measurements (every 8 weeks, i.e. within 7 days prior to C9D1, C13D1 etc.).  
Upon documentation of radiographic progression, confirmatory tumor measurements to 
be repeated at 4 weeks +/- 3 days only for patients who elect to continue on therapy until 
confirmation of progression. If this scan confirms progression, treatment is to be 
discontinued. If the confirmatory measurements indicate stable disease or better, the 
patient may elect to continue treatment with radiographic tumor assessments every 8 
weeks from Day 1 of the current treatment cycle until progression. 
 
End of Study Visit- This visit should be completed within 14 days for any subject who elects to 
come off trial or who comes off due to AEs, toxicities, or decline in performance status: 
 
• 
Physical Exam 
• 
Weight 
• 
Vital Signs 
• 
ECOG Evaluation 
• 
Hematology panel: CBC with differential, platelets  
• 
Chemistry panel 
• 
Urinalysis  
• 
CRP  
• 
Adverse Event monitoring 
• 
Serum Pregnancy 
• 
PK Sampling 
• 
EORTC QLQ-C30 
• 
Concomitant Medications / Non-Drug Therapies review 
• 
DEXA Scan--for any subject who completes visits at least through C3D1, but 
discontinues prior to C5D1 
• 
Tumor Measurements--for subjects with clinical progression, every effort should be made 
to obtain radiographic restaging. If subjects are discontinued due to evidence of 
progressive disease, then tumor measurements do not need to be repeated. 
 
 
 
Follow up for Overall Survival 
 
Subjects, who come off trial for any reason after C1D1, will be contacted by phone after 30 days 
of the last dosing visit for adverse events and ECOG performance status, and at every 4-6 weeks 


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there after to assess ECOG performance status. Patients will be considered lost to follow up after 
3 documented consecutive unsuccessful contact attempts. Prior to any interim analysis, and once 
the trial has been completed, any subjects who have been lost to follow up will be queried against 
the Social Security Administration’s Death Master File to determine date of death. 


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5.4 STUDY CALENDAR  
Study Procedures 
Screening 
Cycles 1-4 
Cycle 5 
Cycle 6+ 
End of Study Visit 
Follow-Up for 
Survival 
Day -14  
(C1D1) must occur within 7 days 
of randomization: 
Day 1 
(+/- 2 days) 
Day 1 
(+/- 2 days) 
Day 1 
(+/- 2 days) 
Within 14 days of 
treatment 
discontinuation 
Every 4-6 Weeks 
Study Drug Infusion 
 
X 
X 
X 
 
 
Informed Consent 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Serum Pregnancy Testd 
X 
Xd 
Xd 
Xd 
X 
 
Physical Exam 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
 
Vital Signsa 
X 
Xa 
Xa 
Xa 
X 
 
ECOG Evaluation 
X 
X 
X 
X 
X 
X 
Hematology Panel: CBC with 
differential, platelets 
X 
X 
X 
X 
X 
 
Chemistry Panelb 
Xb 
Xb 
Xb 
Xb 
Xb 
 
PT/aPTT/INR 
X 
 
 
 
 
 
Urinalysisc 
Xc 
Xc 
Xc 
Xc 
Xc 
 
PK Samplinge 
 
Xe 
Xe 
Xe 
Xe 
 
CRPf 
Xf 
Xf 
Xf 
Xf 
Xf 
 


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DEXA Scang 
Xg 
 
Xg 
 
Only Patients that 
discontinue between 
C3D1 and C5D1 
 
EORTC-QLQ-C30h 
X 
 
X 
 
 
 
Tumor Measurementsi, j, k 
Xi 
 
Xi 
After DEXA scan 
Xi, j 
Every 8 Weeks 
Xj, k 
Unless discontinued for 
Progressive Disease 
 
Adverse Events  
X 
Concomitant Medications  
X 
 
 


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Footnotes for Study Calendar: 
a Blood pressure, pulse and temperature. Pre and 60 minutes post infusion. 
b Sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, calcium, magnesium, albumin, alkaline phosphatase, total bilirubin, SGOT [AST], and SGPT [ALT] 
will be analyzed locally as standard of care for safety prior to infusion. A second pre-infusion sample must be obtained and shipped to the central lab. 
c Bilirubin, glucose, ketones, leukocytes, nitrites, blood, pH, specific gravity, protein and urobilinogen will be analyzed will be analyzed locally as standard of care for 
safety prior to infusion. A second pre-infusion sample must be obtained and shipped to the central lab. 
d Pregnancy Test Every 2 Cycles. Sample sent to the central lab for chemistry will be used for analysis, no additional blood draw required. Results will be sent from 
central lab to the site 
 
e Pre and post-infusion PK samples to be collected. One 6 ml Na-Heparin tube will be used to collect blood from subjects at each PK sampling time point. Note: during 
visits when subjects are receiving MABp1, the “post-infusion” sample will be collected between 30-90 minutes post-infusion. 
f CRP will be assayed from the Chemistry sample on Screening, Cycles 1-5, Cycles 6+, End of Study/Early Termination and Unscheduled Visits. 
g DEXA scans will be performed at screening and at Cycle 5 Day 1 (+/- 3 days) to assess changes in body composition. To qualify for inclusion, a site’s DEXA should 
include the following compartments: bone, fat, and lean. Results are reported in grams, and should be reported for each extremity, trunk, head, and total, to allow for 
determination of an axial skeletal muscle index. Patients should be scanned with the same DEXA machine using the same software version, at each measurement. 
DEXA scans should be scheduled to occur prior to CT or MRI tumor measurements. In the event that a CT scan with contrast is obtained prior to a DEXA scan (such as 
scans done for standard of care), then there must be a 10 day washout prior to obtaining the DEXA scan. Subjects who discontinue study prior to C3D1 will not 
receive a second DEXA scan. An off study lean body mass/body composition DEXA scan should be performed at the End of Study Visit for any subject who completes 
visits at least through C3D1, but discontinues prior to the C5D1 DEXA. 
h The EORTC QLQ-C30 (version 3) is a validated quality of life instrument for cancer patients. It consists of 30 items that encompass 3 symptom scales (pain, fatigue, 
nausea/vomiting), 6 single-item symptom items, 5 functional scales (physical, cognitive, role, emotional, and social), and one scale assessing global health status/quality 
of life. Each scale consists of 2-5 items. All items have four response categories (not at all, a little, quite a bit, very much), except for 2 items assessing overall health 
status/quality of life, which use a seven-point scale. 
i Assessments can include CT or MRI, and whichever modality is chosen for the initial tumor assessment must be used for the week 8 assessment (Cycle 5 Day 1). 
Tumor measurements should ideally be obtained after DEXA scans for body composition. If standard of care scans are used, then there should be a 10-day washout 
after any CT scan with contrast prior to obtaining the DEXA scan. The choice of modality should be based primarily on the type of scan that the patient has previously 
received as their standard of care. Standard of care scans obtained within 28 days of C1D1 can be used as screening scans.  Tumor measurements are to be performed 
on Cycle 5 Day 1 +/- 3 days. 
j Following Cycle 6 Day 1, tumor measurements are to be repeated every 8 weeks (within 7 days prior to C9D1, C13D1, C17D1, etc.). Upon documented progression, 
confirmatory tumor measurements are to be repeated at 4 weeks +/- 3 days, for patients who elect to continue therapy until confirmation of progression. 
k Tumor measurements should be performed, if possible, for subjects with clinical progression, to obtain radiographic restaging. 


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6. CORRELATIVE STUDIES 
 
6.1 PHARMACOKINETICS (PK) SAMPLE COLLECTION 
 
An enzyme-linked immunosorbent assay (ELISA) has been developed to specifically measure 
MABp1 levels in human plasma. Six milliliters of blood will be drawn into a single Na-Heparin 
treated tube at each PK collection time point (there are two collection time points at each infusion 
visit). These samples will be processed and plasma will be sent to a core laboratory for temporary 
storage, and will then be shipped to XBiotech in monthly batches for PK analysis. In addition to 
plasma levels of MABp1, these samples will be used to test for the presence of antibodies against 
MABp1, as well as baseline IL-1Ra levels. 
 
Pharmacokinetics samples will be taken in all patients. The pharmacokinetics of MABp1 in 
plasma will be randomly analyzed. Plasma samples will also be randomly monitored for the 
development of anti-MABp1 antibodies.  If the study meets the primary endpoint, then all 
samples will be tested in order to develop a population pharmacokinetic model. 
 
 
7. CRITERIA FOR EVALUATION 
 
7.1 SAFETY DATA MONITORING 
 
Local labs for safety will be done prior to infusion. A 2nd sample will be taken and shipped to the 
central lab for analysis. Blinded lab and adverse event data will be reviewed at regular intervals 
by the Sponsor’s Medical Safety Officer. Teleconferences will be held as needed between the 
Sponsor and the National Principal Investigator to discuss adverse events or any laboratory trends 
that develop. An independent data monitoring committee will also review unblinded safety and 
efficacy data at specified time points. See section 10, “Statistical Analysis”, for a complete 
discussion. 
  
7.2 MEASUREMENT OF EFFECT  
 
The difference in median overall survival between the MABp1 + BSC group will be compared to 
the placebo + BSC group. See section 10, “Statistical Analysis”, for a complete discussion. 
 
7.3 RADIOGRAPHIC ASSESSMENT OF BODY COMPOSITION 
 
Dual energy X-ray absorptiometry (DEXA) is an X-ray imaging modality used to determine the 
mass of one material in the presence of another material, using the knowledge of their unique X-
ray attenuation at different energies36. DEXA is an extremely accurate and precise method for 
measuring body composition, with a coefficient of variation for serial measurements of lean body 
mass between 0.4% and 1.3%37.  
 
 
 
 


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Figure 7.1 
 
 
This figure illustrates the basic principle of DEXA scanning. The X-ray beam is projected 
through the body, and the amount of attenuation by tissue compartment is measured by the 
detector (Toombs. Et al.). 
 
DEXA scans will be performed at screening and at week 8 to assess changes in body 
composition. To qualify for inclusion, a site’s DEXA should include the following compartments: 
bone, fat, and lean. Results are reported in grams, and should be reported for each extremity, 
trunk, head, and total, to allow for determination of an axial skeletal muscle index. Patients 
should be scanned with the same DEXA machine using the same software version, at both 
screening and week 8. 
 
Investigative sites will be required to provide documentation of their scanners last calibration 
report by the manufacturer, as well as a QC reports that confirm that the scanner is still 
performing according to the manufacturer’s specifications (i.e. scans of QC phantoms).  
 
DEXA scans should not be performed if a patient has received intravenous or oral contrast 
within the previous 10 days. 
 
7.4 QUALITY OF LIFE ASSESSMENT  
 
Quality of life, including measurement of cancer related fatigue, will be assessed using the 
EORTC QLQ-C30 questionnaire (version 3). This questionnaire is a validated quality of life 
instrument for assessment of cancer related symptoms. It consists of 30 items that encompass 3 
symptom scales (pain, fatigue, nausea/vomiting), 6 single-item symptom items, 5 functional 
scales (physical, cognitive, role, emotional, and social), and one scale assessing global health 
status/quality of life. Each scale consists of 2-5 items. All items have four response categories 
(not at all, a little, quite a bit, very much), except for 2 items assessing overall health 
status/quality of life, which use a seven-point scale. 
 
The patient should complete the EORTC questionnaire without prompting from the site staff.  
After completion, the site staff will confirm that all questions have been answered prior to the 
patient leaving. If there are any incomplete items, the staff should request that the patient 
complete these prior to leaving this visit. 
 


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7.5 RADIOGRAPHIC MEASUREMENT OF TUMOR SIZE  
 
Tumor response will be assessed by comparison of radiographic measurements of tumor size at 
baseline and measurements performed approximately every 8 weeks during study treatment and 
at specified time points following progression. 
 
A Central Imaging Vendor will complete tumor measurements and only results of progression or 
stable disease will be reported back to the sites.  
 
Definitions 
 
Response and progression will be evaluated in this study using the Immune Related Response 
Criteria (irRC). 
 
Measurable Disease 
 
Index lesions: Must be accurately measured in two dimensions, with a minimum size of ≥10 x 
10mm (two largest perpendicular diameters) by CT scan (CT scan slice thickness no greater than 
5 mm) or 10mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable). 
 
Non-measurable Disease 
 
All other lesions, including small lesions (longest diameter <10mm, <5x5 mm bidimensionally, 
or pathological lymph nodes with ≥10 to <15mm short axis) as well as truly non-measurable 
lesions. Lesions considered truly non-measurable include: leptomeningeal disease, ascites, pleural 
or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, or 
abdominal masses/abdominal organomegaly identified by physical exam that is not measurable 
by reproducible imaging techniques. 
 
Index and non-Index Lesions: 
 
At the baseline (screening) tumor assessment, the dimensions of the two largest perpendicular 
diameters of all index lesions (five lesions per organ, up to 10 visceral lesions and five cutaneous 
index lesions) will be measured and recorded. At the subsequent (week 10) tumor assessments, 
these measurements will be repeated, along with measurements of the two largest perpendicular 
diameters for any new, measurable lesions (≥10 x 10 mm; up to 5 new lesions per organ: 5 new 
cutaneous lesions and 10 visceral lesions). 
 
Guidelines for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 3 weeks (21 Days) before the beginning of the treatment (C1D1).  
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess the 
antitumor effect of a treatment. 
 


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Clinical lesions. Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes). In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Helical (or Spiral) CT and MRI. These techniques should be performed with cuts of 5 mm or 
less in slice thickness contiguously. Spiral CT should be performed using a ≤5 mm contiguous 
reconstruction algorithm. This applies to tumors of the chest, abdomen, and pelvis. Head and 
neck tumors and those of extremities usually require specific protocols. 
 
7.5.1 Immune Related Response Criteria: 
 
Evaluation of Target Lesions 
 
Evaluation of radiographic response will be conducted using the Immune Related Response 
Criteria (irRC), as described by Wolchok, et al60. “For irRC, only index and measurable new 
lesions are taken into account. At the baseline tumor assessment, the sum of the products of the 
two largest perpendicular diameters (SPD) of all index lesions (five lesions per organ, up to 10 
visceral lesions and five cutaneous index lesions) is calculated. At each subsequent tumor 
assessment, the SPD of the index lesions and of new, measurable lesions (≥10 x 10mm; up to 5 
new lesions per organ: 5 new cutaneous lesions and 10 visceral lesions) are added together to 
provide the total tumor burden:” 
 
Tumor Burden=SPDindex lesions + SPDnew, measurable lesions 
 
Complete Response (irCR): irCR, complete disappearance of all lesions (whether measurable or 
not, and no new lesions). Confirmation by a repeat, consecutive assessment no less than 4 weeks 
from the date first documented. 
 
Partial Response (irPR): irPR, decrease in tumor burden ≥50% relative to baseline confirmed by a 
consecutive assessment at least 4 weeks after first documentation. 
 
Progressive Disease (irPD): irPD, increase in tumor burden ≥25% relative to nadir (minimum 
recorded tumor burden) confirmation by a repeat, consecutive assessment no less than 4 weeks 
from the date first documented. 
 
• 
If a patient is classified as having irPD at a post-baseline tumor assessment, then 
confirmation of irPD by a second scan in the absence of rapid clinical deterioration is 
required. The definition of confirmation of progression represents an increase in tumor 
burden ≥25% compared with the nadir at two consecutive time points at least 4 weeks 
apart. It is recommended that this be done at the discretion of the investigator 
because follow-up with observation alone may not be appropriate for patients with a 
rapid decline in performance status. 
 
Stable Disease (irSD): irSD, not meeting criteria for irCR or irPR, in absence of irPD. 
 
 
 


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8. SAFETY AND TOLERABILITY 
 
As of the last Development Safety Update Report, over 500 patients have been treated with 
Xilonix™ and over 2100 doses have been administered. The safety profile observed so far has 
been excellent. There have been no infusion reactions reported with the i.v. administration of the 
antibody (subjects are not pre-medicated with antihistamines or steroids) and there have been few 
injection site reactions reported with the subcutaneous formulation. These observations are highly 
consistent with the fact that there have been no human anti-human antibodies against Xilonix™ 
detected. 
 
The adverse events reported vary by disease indication, but most of the events appear related to 
the underlying disease and there are no severe or serious toxicities that are obviously related to 
therapy with Xilonix™.   
 
IL-1α is a key mediator of sterile inflammatory responses, however immunosuppression had been 
considered as a theoretical risk of the antibody. To date there is no evidence of 
immunosuppression or increased susceptibility to infection of any kind in patients treated with 
Xilonix™. 
 
Platelets and other peripheral blood cells, including neutrophils and macrophages, may express 
IL-1α and thus may be targeted by Xilonix™. While there is no evidence that Xilonix™ induces 
antibody-directed cellular cytotoxicity, there may be the potential for Xilonix™ to cause 
thrombocytopenia, monocytopenia or neutropenia in some patients, however, this has not been 
observed to date.  
 
An expanded discussion of potential risks and monitoring with Xilonix™ therapy is located in 
Section 4.6 of the Investigator’s Brochure. 
 
The following sections contain summary adverse event tables for two trials of Xilonix™ in patients 
with solid tumors. Summary tables for all trials in all indications using Xilonix™, as well as safety 
conclusions are located in sections 2.1-2.8 of the Investigator’s Brochure.   
 
8.1 ONCOLOGY (SOLID TUMOR) DATA: 
 
The study 2009-PT004 was an open label, dose escalation trial of Xilonix™ in patients with 
advanced cancer. To be eligible, a patient was required to have metastatic disease that was 
refractory to all standard of care therapies. Patients at a single center in the US were dosed with 
0.25, 0.75, 1.25 and 3.75 mg/kg of intravenous Xilonix™ every three weeks, and 3.75 mg/kg IV 
every two weeks. Phase 2 expansion cohorts were explored at the 2 highest doses. A total of 52 
patients were treated, and >300 doses of Xilonix™ were administered. 
 
 
 
 
 
 
 
 
 
 


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Table 8.1: Summary of Adverse Events (Solid Tumor) 
 
MedDRA Preferred Term 
(2009-PT004) 
AEs by CTCAE Grade (% of total subjects, n=52) 
Grade I-II 
Grade III 
Grade IV 
Grade V 
Fatigue 
15 (28.8%) 
2 (3.8%) 
1 (1.9%) 
0 (0.0%) 
Proteinuria 
12 (23.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Nausea 
10 (19.2%) 
1 (1.9%) 
0 (0.0%) 
0 (0.0%) 
Edema peripheral 
7 (13.5%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Constipation 
6 (11.5%) 
1 (1.9%) 
0 (0.0%) 
0 (0.0%) 
Anorexia 
6 (11.5%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Dyspnea 
6 (11.5%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Hyperkalemia 
6 (11.5%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Vomiting 
6 (11.5%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Hypoalbuminemia 
5 (9.6%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Thrombocytopenia 
4 (7.7%) 
1 (1.9%) 
0 (0.0%) 
0 (0.0%) 
Leukocytosis 
4 (7.7%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Anemia 
3 (5.8%) 
1 (1.9%) 
0 (0.0%) 
0 (0.0%) 
Diarrhea 
3 (5.8%) 
0 (0.0%) 
1 (1.9%) 
0 (0.0%) 
Cough 
3 (5.8%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Decreased appetite 
3 (5.8%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Edema peripheral 
3 (5.8%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Hyperbilirubinemia 
3 (5.8%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Myalgia 
3 (5.8%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Transaminases increased 
3 (5.8%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Urinary tract infection 
3 (5.8%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Pain 
2 (3.8%) 
2 (3.8%) 
0 (0.0%) 
0 (0.0%) 
Headache 
2 (3.8%) 
1 (1.9%) 
1 (1.9%) 
0 (0.0%) 
Aspartate aminotransferase 
increased 
2 (3.8%) 
1 (1.9%) 
0 (0.0%) 
0 (0.0%) 
Lymphopenia 
2 (3.8%) 
1 (1.9%) 
0 (0.0%) 
0 (0.0%) 
Pneumonia 
2 (3.8%) 
1 (1.9%) 
0 (0.0%) 
0 (0.0%) 
Weakness 
2 (3.8%) 
1 (1.9%) 
0 (0.0%) 
0 (0.0%) 
Blood alkaline phosphatase 
increased 
2 (3.8%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Dyspepsia 
2 (3.8%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Gastroesophageal reflux 
disease 
2 (3.8%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Hypokalemia 
2 (3.8%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Hyponatremia 
2 (3.8%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Neuropathy peripheral 
2 (3.8%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Rash 
2 (3.8%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Renal failure acute 
1 (1.9%) 
1 (1.9%) 
0 (0.0%) 
0 (0.0%) 
Dyspnea 
0 (0.0%) 
2 (3.8%) 
0 (0.0%) 
0 (0.0%) 


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Delayed recovery from 
anesthesia 
0 (0.0%) 
1 (1.9%) 
0 (0.0%) 
0 (0.0%) 
Focal seizures 
0 (0.0%) 
1 (1.9%) 
0 (0.0%) 
0 (0.0%) 
Gastrointestinal hemorrhage 
0 (0.0%) 
1 (1.9%) 
0 (0.0%) 
0 (0.0%) 
Cramps Leg 
0 (0.0%) 
0 (0.0%) 
1 (1.9%) 
0 (0.0%) 
Disease progression 
0 (0.0%) 
0 (0.0%) 
1 (1.9%) 
0 (0.0%) 
Disease progression/death 
0 (0.0%) 
0 (0.0%) 
1 (1.9%) 
0 (0.0%) 
Ear pruritus 
0 (0.0%) 
0 (0.0%) 
1 (1.9%) 
0 (0.0%) 
Muscle Cramp 
0 (0.0%) 
0 (0.0%) 
1 (1.9%) 
0 (0.0%) 
Death 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (1.9%) 
 
 
Safety Conclusions 
 
Adverse events observed in this trial were consistent with what would be expected in an advanced 
cancer population and there was no evidence that the antibody had any probable relation to AEs 
of any kind. The most common AE was proteinuria, and 4 of 12 events were grade II (2+) as 
measured by urine dipstick. Two of these patients, however, had ureteral stents and a large 
amount of blood (3+) in urinalysis; one had proteinuria performed just prior to the first infusion, 
and the last one had a history of proteinuria for 6 months prior to entering the study. The 
remaining 7 (17%) patients had grade I (1+) proteinuria, which correlates poorly with confirmed 
microalbuminuria38. The majority of these patients had previously been treated with Avastin as 
well. A randomized trial will clarify whether or not proteinuria is an actual consequence of 
Xilonix™ therapy. 
 
The following table shows safety data from V2.4 of the PT023 trial. This version of the trial 
enrolled patients with metastatic colorectal cancer and concomitant cachexia (>5% weight loss in 
previous 6 months). Patients were randomized 1:1 to receive Xilonix™ + best supportive care 
versus megestrol acetate + best supportive care. Best supportive care included 3+ line 
chemotherapies, such as cetuximab or regorafenib. Adverse events are presented for both the 
Xilonix™ (N=20) and megestrol (N=20) arms. This data is preliminary as patients are still on 
study, and the data is still undergoing monitoring and cleaning. 
 
 
Table 8.2: Summary of Xilonix™ AEs (CRC with Cachexia) 
 
MedDRA Preferred Term 
(2012-PT023; MABp1 Arm) 
AEs by CTCAE Grade  
(% of total subjects, n=20) 
Grade I-II 
Grade III 
Grade IV 
Grade V 
Nausea 
7 (35.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Vomiting 
7 (35.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Abdominal pain 
5 (25.0%) 
2 (10.0%) 
0 (0.0%) 
0 (0.0%) 
Fatigue 
5 (25.0%) 
2 (10.0%) 
0 (0.0%) 
0 (0.0%) 
Diarrhea 
4 (20.0%) 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
Chills 
3 (15.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Alopecia 
2 (10.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Back pain 
2 (10.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Constipation 
2 (10.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 


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Dehydration 
2 (10.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Dizziness 
2 (10.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Edema limbs 
2 (10.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Pain 
2 (10.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Palmar-plantar erythrodysaesthesia 
syndrome 
2 (10.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Ascites 
1 (5.0%) 
2 (10.0%) 
0 (0.0%) 
0 (0.0%) 
Chest pain - cardiac 
1 (5.0%) 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
Dyspnea 
1 (5.0%) 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
Skin and subcutaneous tissue 
disorders  
1 (5.0%) 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
Acidosis 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Alkaline phosphatase increased 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Anemia 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Anorexia 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Anxiety 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Blood and lymphatic system 
disorders  
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Blood bilirubin increased 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Cardiac disorders  
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Confusion 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Cough 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Creatinine increased 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Dysgeusia 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Endocrine disorders 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
ERYTHRODYSESTHESIA 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Fall 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Fecal incontinence 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Fever 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Gait disturbance 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Gastrointestinal disorders  
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Hypertension 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Hypoalbuminemia 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Hyponatremia 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Laryngeal hemorrhage 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Musculoskeletal and connective 
tissue disorder 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Neck pain 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Neutropenia 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Palpitations 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Rash 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Sinus disorder 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Skin hyperpigmentation 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Somnolence 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Stomach pain 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Upper respiratory infection 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Urinary incontinence 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Weight loss 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Wheezing 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Small intestinal obstruction 
0 (0.0%) 
2 (10.0%) 
0 (0.0%) 
0 (0.0%) 
Bone pain 
0 (0.0%) 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
Hyperglycemia 
0 (0.0%) 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
Hypotension 
0 (0.0%) 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
Nervous system disorders 
0 (0.0%) 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
Cardiac arrest 
0 (0.0%) 
0 (0.0%) 
1 (5.0%) 
0 (0.0%) 
Upper gastrointestinal hemorrhage 
0 (0.0%) 
0 (0.0%) 
1 (5.0%) 
0 (0.0%) 
Death 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (5.0%) 
 
 


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Table 8.3: Summary of Megace AEs (CRC with Cachexia) 
 
MedDRA Preferred Term 
(2012-PT023; Megestrol Arm) 
AEs by CTCAE Grade  
(% of total subjects, n=20) 
Grade I-II 
Grade III 
Grade IV 
Grade V 
Dyspnea 
5 (25.0%) 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
Fatigue 
4 (20.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Hypertension 
3 (15.0%) 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
Back pain 
3 (15.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Urinary tract infection 
3 (15.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Diarrhea 
2 (10.0%) 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
Constipation 
2 (10.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Cough 
2 (10.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Gastroesophageal reflux disease 
2 (10.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Headache 
2 (10.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Nausea 
2 (10.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Palmar-plantar erythrodysaesthesia 
syndrome 
2 (10.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Abdominal pain 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Acute kidney injury 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Alopecia 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Anemia 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Bronchial infection 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Bruising 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Dry skin 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Erythema multiforme 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Fall 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Haematochezia 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Hoarseness 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Hypokalemia 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Hypoxia 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Insomnia 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Mucositis oral 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Musculoskeletal and connective 
tissue disorder  
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Non cardiac chest pain 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Pain 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Peripheral sensory neuropathy 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Prostate infection 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Rash 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Rectal pain 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Sinus Tachycardia 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 


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Skin infection 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Sore throat 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Spasticity 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Tumor pain 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Vomiting 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Weight gain 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Hypovolaemia 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Hyperglycemia 
0 (0.0%) 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
Leukocytosis 
0 (0.0%) 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
Thromboembolic event 
0 (0.0%) 
1 (5.0%) 
0 (0.0%) 
0 (0.0%) 
Obstruction gastric 
0 (0.0%) 
0 (0.0%) 
1 (5.0%) 
0 (0.0%) 
Death 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (5.0%) 
Disease progression 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (5.0%) 
 
 
At this point there have been no adverse trends identified in this study. The adverse events 
reported appear to be related to the underlying disease, or related to concomitant chemotherapy. 
 
 
8.2 REFERENCE SAFETY INFORMATION: POTENTIAL ADVERSE REACTIONS 
 
Over 500 patients have been treated using Xilonix in patients with advanced solid tumors, 
advanced hematologic malignancies, metastatic colorectal cancer, peripheral vascular disease, 
type II diabetes, acne vulgaris, plaque psoriasis, and pyoderma gangrenosum.  Over 1200 doses of 
Xilonix were administered at 7.5 mg/kg to refractory, metastatic CRC patients with cancer 
associated symptoms at baseline (ECOG performance status 1 and 2).  In this trial (PT026), 
which is the largest controlled trial completed with Xilonix to date (N=309), patients were dosed 
at 7.5 mg/kg for metastatic colorectal cancer.  The most common AEs reported (>10%) were 
abdominal pain, peripheral edema, fatigue, anemia, constipation, decrease in weight, asthenia, 
decreased appetite, and nausea.  The majority of these events were grade 1 or 2, and appeared to 
be related to the underlying CRC.  The prevalence of these events was similar in the Xilonix and 
placebo groups.  Two infusion reactions were reported in this trial, and they were not serious or 
severe (grade I or II). 
 
The RSI has been updated based upon data from a randomized, double-blind, placebo controlled 
trial in metastatic colorectal cancer (2014-PT026), which was recently completed.  In this trial, 
there was no difference in the incidence of thrombocytopenia, proteinuria, nausea, or diarrhea, 
between the two groups; therefore these terms were removed from the list of expected adverse 
reactions (ARs).  There were two infusion reactions that occurred in the PT026 trial, as well as one 
infusion reaction reported as an SAE in the PT023 trial.   
The mechanism behind infusion reactions is not clear in all cases.  It may involve a reaction 
against the antibody products themselves, or, against some minor residual component from the 
manufacturing process (i.e. host cell proteins).  To date, after administration to over 500 patients, 
and over 3000 doses, the risk of infusion reaction remains extremely low.  


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For the purposes of expedited safety reporting in clinical trials, the following should be 
considered expected events: 
 
• 
Infusion Related Reactions 
 
Refer to Section 4.6 of the Investigator’s Brochure for clinical trial summaries of Xilonix, and 
Section 5 for a Summary of Data and Guidance for the Investigator. 
 
8.3 Overall Risk and Benefit Assessment 
 
Chemotherapy and radiotherapy in the context of advanced metastatic or unresectable colorectal 
cancer is largely palliative—meaning that complete eradication of the tumor is not expected. The 
primary goal in this setting is reducing symptomatic effects of the tumor for as long as possible. 
Due to toxicity, however, these treatment modalities are poorly suited for this objective. Even 
with the most recent agents (such as multi-kinase inhibitors) treatment related morbidity often 
results in discontinuation of therapies— ultimately leading to uncontrolled progression and death. 
New agents that exhibit anti- neoplastic activity and provide improvement in tumor related 
symptoms are vitally needed to treat this and other advanced cancer populations.  
 
Specific antagonism of IL-1α through XilonixTM therapy is viewed as a unique, broad acting 
tumor suppression strategy that encompasses significant activity to ameliorate symptoms 
associated with the disease, as well as improve overall survival. IL-1α is unique in its 
involvement in so many processes related to tumor progression and collateral symptomatic effects 
of malignancy. The excellent safety and tolerability profile of the agent make it an ideal treatment 
option in advanced stage disease, particularly where the use of cytotoxic or other therapies with 
considerable toxicity are not supported by the risk benefit profile.  
 
Blocking IL-1α appears to normalize the metabolic energy balance with the net accumulation of 
lean body mass (LBM). An average LBM increase of 1.9±2kg was seen in 70% of patients treated 
(p<0.001) compared to their baseline values. These same patients had improvements in pain, 
anorexia, and fatigue as measured by the EORTC- QLQ-C30. Traditional, radiographic evidence 
of anti-tumor activity was also noted, with 21% of patients having stable disease for 3 months or 
greater, including a partial response in a patient with metastatic colorectal cancer. Additionally, 
colorectal cancer patients with improvements in LBM had a trend towards a clinically significant 
overall survival benefit.  
 
For this agent, this reversal of tumor related symptoms, is viewed as the direct result of an anti-
neoplastic mechanism of action and is potentially a more powerful surrogate for clinical benefit 
than traditional radiographic based assessments.. In the tumor microenvironment IL-1α driven 
sterile inflammation results in neoangiogenesis and tissue matrix remodelling both of which are 
critical for tumor growth. Within the vascular space, membrane associated IL-1α on PBMCs and 
platelets activate vascular endothelium, which in turn leads to upregulation of adhesion molecules 
and further infiltration of the microenvironment by pro-tumor inflammatory cells. Activation of 
the vascular endothelium also provides a mechanism by which tumor cells (in the form of tumor-
platelet microemboli) can escape into new areas of metastasis.  
 
The importance of IL-1α to tumor growth and invasiveness has been illustrated in numerous pre-
clinical models, as well as from studies examining biopsies of multiple tumor types. However, the 
most compelling evidence to date is that illustrated in our pilot oncology trial, 2009-PT004. 


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Radiographic evidence of tumor regression has been observed in some cases, and multiple 
patients have experienced prolonged stable disease. Adverse events observed in these oncology 
patients have been mild, with 97% being grade 2 or lower in severity. These events have also 
shown no obvious relation to study drug administration.  
Xilonix is a non-toxic, anti-neoplastic agent that has shown preliminary evidence of improving 
both metabolic and functional symptoms in patients who have exhausted all lines of anti-tumor 
therapy. The demonstration of LBM increases in advanced stage patients with a non-anabolic 
agent could represent a significant milestone in the management of metastatic cancer, as well as a 
novel surrogate for anti-neoplastic activity in refractory patients. Based upon these observations, 
the risk benefit analysis of Xilonix appears to be favourable and this therapy should be explored 
further advanced cancer patients.  
 
 


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9. ADVERSE EVENTS  
 
9.1 DEFINITION OF ADVERSE EVENT (AE) 
 
An adverse event is defined as any new or worsening untoward medical occurrence in a subject 
participating in a clinical study that does not necessarily have a causal relationship with the 
pharmaceutical or biological agent under study. An AE can therefore be any of the following: 
 
• 
Any unfavorable and unintended sign (including laboratory findings), symptom, or disease 
temporally associated with the use of MABp1, whether or not it is apparently related to 
MABp1 
• 
A concurrent illness 
• 
An exacerbation, or an unexpected increase in frequency or intensity of a preexisting 
condition, including intermittent or episodic conditions.  
• 
A significant or unexpected worsening of the condition/indication under investigation.  
However, anticipated day-to-day fluctuations or non-serious, expected progression of the 
disease under investigation (based upon the Investigator’s clinical judgment) are not to be 
considered AEs 
• 
A suspected interaction between the investigational drug and concomitant medications 
• 
Any clinically significant laboratory abnormality (including radiological interpretations, 
histopathological findings, etc.) 
 
9.2 DEFINITION OF SERIOUS ADVERSE EVENT (SAE) 
 
A serious adverse event is defined as any untoward medical occurrence that meets any of the 
following criteria:  
 
• 
Results in death 
• 
Life-threatening 
• 
Requires or prolongs inpatient hospitalization 
• 
Results in a persistent or significant disability or incapacity 
• 
Congenital anomaly/birth defect or 
• 
An important medical event that, while it may not result in death or be immediately life-
threatening or require/prolong hospitalization, may jeopardize the subject and/or may 
require medical or surgical intervention to prevent one of the outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or the development of drug dependency or drug abuse. 
 
Note that seriousness and severity should not be confused. A subject could experience a severe 
headache that would not qualify as an SAE, while another might experience a mild stroke that, 
while not severe, would be considered serious. 
 
9.3 RECORDING OF ADVERSE EVENTS 
 
All untoward events occurring between Cycle 1 Day 1 and 30 days following the last 
administration of the investigational drug must be recorded on the eCRF, regardless of whether 
they are considered related to study drug or not.   
 


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All AEs should be recorded in a standard medical terminology as concisely as possible. The AE 
recorded should not be a procedure or a clinical/laboratory measurement, but should reflect the 
event leading to the procedure or the cause of the clinical/laboratory abnormality, if known.   
 
Whenever possible, AEs should be evaluated and recorded as a diagnosis, rather than individual 
signs and symptoms. However if a definitive diagnosis is not possible, the individual signs and 
symptoms should be recorded. Any AE that worsens in intensity, or becomes serious, should be 
recorded as a new event. 
 
9.4 EVALUATING ADVERSE EVENTS 
 
All AEs will be graded according to the CTCAE version 4.0. 
 
9.5 ASSESSMENT OF CAUSALITY 
 
Investigators are required to assess the relationship, if any, of each AE or SAE to the 
investigational drug using clinical judgment to determine the degree of certainty with which an 
AE can be attributed to the investigational drug. Alternative causes, such as natural history of the 
underlying disease, other risk factors, and the temporal relationship of the event to the 
administration of the study medication must be considered. 
 
Relationship to study drug is summarized as follows: 
 
• 
Not Related: There is another obvious cause of the AE 
• 
Unlikely to be related: There is another more likely cause of the AE 
• 
Possibly related: The AE could have been due to the investigational drug 
• 
Probably related: The AE is probably attributable to the investigational drug 
• 
Definitely related: The AE is most likely attributable to the investigational drug 
 
9.6 REPORTING REQUIREMENTS  
 
All serious adverse events (SAEs) should be reported to the Sponsor within 24 hours of 
knowledge of the event. These immediate reports should be followed promptly by detailed, 
written reports. The immediate and follow-up reports should identify subjects by unique code 
numbers assigned to the trial subjects rather than by the subjects' names, personal identification 
numbers, and/or addresses. The Investigator should also submit SAEs to the IRB/EC according to 
their IRB/EC guidelines [ICH-GCP E6]. Drug-related Serious Adverse Events will be reported to 
the FDA by XBiotech’s Medical Safety Officer according .32. 
 
9.7 SAFETY LEAD IN PLAN 
 
In order to more accurately characterize the adverse event profile at the 7.5 mg/kg dose level, the 
Sponsor will conduct a blinded review of adverse event data for the first 10+10 patients enrolled 
on this protocol at that dose level. Review of the data will occur after completion of 2 cycles (28 
days) of therapy for the first 10 patients, and then again after the second 10 patients. As there is a 
2:1 randomization, approximately 6 of the first 10 and 13 of the first 20 patients will have 
received Xilonix™. A report of the adverse event data at each of these two time points will be 
submitted to the FDA within 10 days of the last patient’s completion of 2 cycles. 
 


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The Sponsor will voluntarily suspend enrollment on the study, immediately and at any time upon 
review of safety data during the lead in period, if ≥ 33% (≥ 6) of patients have experienced a dose 
limiting toxicity (DLT). In this event, enrollment will be suspended pending further IDMC 
review and pending further guidance from the FDA. Under these circumstances, the IDMC will 
be asked to review un-blinded data and make a recommendation regarding the safety of the dose 
level in this population. 
 
A DLT will be defined as a clinically significant adverse event or abnormal laboratory value 
assessed as unrelated to disease progression, intercurrent illness, or concomitant medications 
occurring during the first two cycles (i.e. 28 days) of therapy, with relationship to study drug 
determined as possible, probable, or definite and meeting the criteria as Grade 3 or Greater 
Hematological or Non-Hematological Toxicity as assessed by the CTCAE V4.0. 
 
 
 


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10. STATISTICAL ANALYSIS 
 
10.1 STUDY DESIGN 
 
This will be a double blind, randomized, placebo controlled, multicenter, parallel-group Phase III 
trial comparing the efficacy and safety of Xilonix™ plus best supportive care (BSC) to placebo 
plus BSC. Consented eligible subjects will be enrolled and randomly assigned to treatment arm or 
placebo arm with 2:1 ratio respectively. Subjects randomized to treatment arm will receive 
Xilonix™ and those in control arm will receive placebo via intravenous infusion every 2 weeks 
(one cycle) plus BSC. Total study duration will be 18 months. An Independent Data Monitoring 
Committee will be formed prior to the study initiation to monitor the safety during study, as well 
as to evaluate the efficacy and safety results at the time of the protocol-specified interim analysis. 
 
10.2 STUDY ENDPOINTS 
 
10.2.1 Primary Efficacy Endpoint: 
 
Overall survival (OS) will be the primary endpoint of this study survival time will be defined as 
the duration from the date of randomization until death. Subjects who are alive at the end of 
follow-up will be censored and survival time will be defined as time from randomization to 
censor date. The overall survival between the Xilonix™ + BSC group and placebo + BSC group 
will be compared using an unadjusted log-rank test.     
 
10.2.2 Secondary Endpoints: 
 
Secondary efficacy variables will include change in lean body mass (LBM) measured by dual-
energy X-ray absorptiometry (DEXA) scans, change in Quality of Life assessed through the 
cancer-specific EORTC QLQ-C30 questionnaire, stabilization of platelet counts, progression free 
survival (PFS), objective response rate (ORR) and disease control rate (DCR).  
 
10.2.3 Exploratory Endpoint: 
 
Clinical Response Rate (CRR) will be the exploratory endpoint for this study. This will be a 
composite measure assessing the change in LBM, fatigue, pain, and appetite from baseline to 
week 8. Clinical response will be defined as, 1) Improvement or stabilization (≥0 kg change) of 
LBM as assessed by DEXA scan, and 2) Improvement or no worsening (≤0 score point change; 
low scores reflect better functioning and lower symptom distress ) on any two of the three 
symptom scale measures (fatigue, pain, appetite) of EORTC QLQ-C30. Patients missing the 
follow-up assessment will be considered non-responders. 
 
10.2.4 Safety Endpoint: 
 
Safety endpoints will be evaluated by monitoring adverse events from clinical and laboratory 
reporting. Adverse events will be classified according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE). Significant trends in the distribution 
and severity of the adverse events across the study groups will be assessed.  
 


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10.3 SAMPLE SIZE AND POWER 
 
Prior research has reported a median survival of 4.6 months among refractory, metastatic 
colorectal cancer patients with BSC in a comparable patient cohort. On the other hand, as 
observed in the colorectal cancer cohort of our phase I/II trial, the median survival was 6.7 
months for all enrolled colorectal cancer patients and 8.7 months for the per-protocol population.  
Using a conservative approach, the current study is designed to detect at least 30% improvement 
in median OS in treatment arm (6.0 months, hazard rate in treatment arm (h1)=0.116)) compared 
to the control arm (4.6 month, hazard rate in control arm (h0)=0.151)). We propose to test the null 
hypothesis for hazard ratio (h1/h0) =1 and alternative hazard ratio ≤ 0.767. With a 2:1 allocation 
ratio and 5% oversampling, a total of 600 subjects (400 and 200 in treatment and control arm 
respectively) will be required to detect the 30% increase in median survival (from 4.6 to 6.0 
months, hazard ratio 0.767) with one-sided Type I error probability (alpha) of 0.025, and 80% 
power (1-beta=0.80). The total number of 552 deaths during the 18 month follow-up in the 
overall study population will provide the above power. The survival curves will be estimated with 
the Kaplan–Meier method and compared for statistical significance by log-rank test.  
 
In contrast to a fixed-sample trial, where the data is analyzed at end of the study, we propose a 
group sequential design that provides for interim analyses before completion of trial while 
maintaining the specified overall Type I and Type II error probabilities.  
 
The trial will have three stages (two interim, one final). As determined based on alpha spending 
function of O’Brien and Fleming sequential group design (O’Brien PC, Fleming TR, 1979), 
survival analyses will be performed after 276 (50%), 414 (75%) and 552 (100%) deaths at the 
respective stages. The efficacy and futility stopping boundaries will be computed separately.  
 
The criteria for the early termination for efficacy (rejection of null hypothesis) or to accept the 
null hypothesis will be based on the group sequential design. If the test statistics crosses the pre-
specified boundaries for type I error (0.0029, 0.010, and 0.012; cumulative alpha of 0.0029, 
0.013, and 0.025 respectively) the trial will stop for efficacy. Otherwise, the trial continues to the 
next stage. The beta levels for stopping the trial for accepting the null hypothesis will be included 
in the detailed statistical analysis plan for the Independent Data Monitoring Committee (IDMC). 
 
If efficacy is established at an interim analysis, enrollment will be stopped and the control group 
will be allowed to crossover. All subjects will be followed up until death, loss to follow-up, or 
termination of the study.  
 
Randomization Strategy: 
 
A central randomization scheme with Interactive Web Response System (IWRS) will be 
employed to facilitate effective randomization and allocation concealment. The scheme will 
involve a block randomization technique, randomly assigning participants within blocks based on 
a 2:1 allocation ratio. The randomization sequence will be generated using Oracle Clinical 
Remote Data Capture application (Oracle Corporation, Redwood City, CA, USA).  
 
10.4 STATISTICAL ANALYSIS PLAN 
 
The primary efficacy analysis will be conducted for the intent-to-treat (ITT) and Per-protocol 
(PP) population.  The ITT population will consist of all randomized patients. The PP population 
will be defined as those patients in the ITT set who are compliant with the study protocol.  


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Given the nature of change to the study design, patients enrolled prior to modification (V3.0) will 
be excluded from the primary efficacy analysis. Those patients will be analyzed separately.   
 
Patient Characteristics and Baseline Comparisons: 
 
The ITT population will be included for analysis of demographic and baseline findings. Data will 
be summarized for each treatment group, i.e. Xilonix™ and placebo arm. Descriptive analysis 
will be performed summarizing age, gender, Eastern Cooperative Oncology Group (ECOG) 
status, co-morbidities, cancer therapy, and other relevant baseline risk factors by treatment group. 
Baseline biochemistry, hematology data will be summarized in separate tables. Continuous 
variables will be reported as mean ± standard deviation (SD), median and inter-quartile range 
(IQR) for non-normal data. The categorical variables will be reported as number of cases (n) and 
percentage. The baseline characteristics will be compared across the groups for overall difference 
by using independent-samples t-test for continuous variables and chi-square test (Fisher’s exact if 
n <20) for categorical data. Normality of the analysis variables will be tested using Shapiro-Wilks 
test. If the Shapiro-Wilks test is significant, continuous data will be compared using Wilcoxon 
(for paired data) and Mann-Whitney nonparametric test. Correlation between parameters was 
evaluated using Spearmann correlation coefficients. A two-tailed p value of <0.05 will be 
considered statistically significant for the descriptive summary statistics. 
 
Efficacy Evaluation: Primary Efficacy Endpoint 
 
Subjects who are alive at the analysis time point the will be censored, and survival time will be 
defined as time from randomization to censor date. Patients, who are lost to follow-up or 
discontinued, will be censored at time of last contact. A censoring variable will be created 
identifying censored observation. The primary endpoint, overall survival, will be summarized by 
Kaplan-Meier method and compared between the treatment groups using un-adjusted log-rank 
test. The median survival, cumulative survival probability and 95% confidence interval (CI), 
calculate by log-log transformation and 25th and 75th percentiles, will be reported according to 
treatment groups. Kaplan-Meier curves will be generated plotting the survival probability and 
probability of occurrence in time. Number of patients at risk on various time intervals will be 
presented on the curve. The type I error rate to be used for determining statistical significance of 
the primary outcome is defined in section 10.3 “interim efficacy analyses”.   
 
A secondary supportive analysis will be performed comparing survival probability across 
treatment groups, stratified by age (dichotomizing by median), gender, ECOG performance 
status, KRAS mutation status, regorafenib and bevacizumab treatment failure status, and number 
of prior antineoplastic therapies. Survival probability and 95% CI for treatment groups will be 
reported for by each stratum.  
 
A multivariate Cox proportional hazards regression (CPH) method will be used for assessing 
independent predictors of OS after adjusting for potential confounders. Selection of covariates 
will primarily be based on a priori knowledge, and include age (continuous scale), prior cancer 
therapy (number of regimens will be entered on continuous scale), ECOG performance status 
(categorical 0-1, 2), baseline IL-1 RA level and KRAS mutation status (coded as no=0, yes=1), 
and baseline body weight (continuous scale). A backward selection method will be used for 
variable selection; the p-value threshold will be set at 0.10. Proportional-hazard assumption will 
be tested by Schoenfeld residual analysis. The hazard ratio (HR) and 95% CI will be computed 
and presented in the results. The CPH analysis will be exploratory in nature. Receiver operating 
characteristic (ROC) analysis will be performed to identify the optimal cut-off of baseline IL-RA 
level that best discriminate overall survival. 


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Efficacy Evaluation: Secondary Efficacy Measures 
 
Secondary endpoints, QoL score and LBM will be evaluated for the absolute change at 8 week 
follow-up on each measure, as well as through a responder analysis comparing objective response 
rate across study arms. 
 
LBM: Patients showing stabilization or improvement from baseline (≥0 kg change) will be 
considered LBM responders. Patients experiencing LBM reduction will be defined as non-
responders. Those not having a second evaluation for going off the study or any other reason, will 
be considered non-responder. Responder rate will be compared using Pearson chi-square test. 
Proportion by group, relative risk and odds ratio estimates will be presented with 95% confidence 
intervals (95% CI).  
 
 
Absolute change will be compared between the Xilonix™ and placebo group using analysis of 
covariance (ANCOVA) method (SAS GLM procedure) with treatment groups as factor and 
baseline value as covariate. The difference in least-square means and 2-sided P values will be 
derived from analysis of covariance model for comparison.  
 
EORTC: The EORTC survey results will be converted to domain specific scores using the 
prescribed algorithm. And scores on EORTC QLQ-C30 functional and symptom scales will be 
summarized according the randomization groups. Score on each scale will be summarized by 
study arms.  
 
Patients showing stabilization or improvement from baseline ( ≤0 change) on any two of the three 
symptom scales (pain, fatigue, appetite) will be considered responders. Patients experiencing 
reduction or worsening will be defined as non-responders. The comparison of responder rate and 
absolute change will performed similar to as described for LBM.  
 
Platelet Count: Change in platelet count from baseline to follow-up will be compared between 
treatment groups using the analysis of covariance method described above. The last visit cycle 
where at least 20 patients per group are on study will be used for follow-up data cut-off for this 
measure. Trend line plots displaying the median platelet count over time (visit cycles) by 
treatment groups will be generated.. 
 
Progression Free Survival (PFS): This will be defined as time from randomization to tumor 
progression or death. Patients surviving without disease progression at end of study will be 
censored. PFS will be compared by Kaplan-Meier method using log-rank test. Kaplan-Meier plots 
by treatment arm will be produced, and point estimates and 95% CIs will be summarized.  
 
Objective Response Rate (ORR): The ORR will be estimated by dividing the total number of 
confirmed complete response (CR) and partial response (PR) by the total number of patients 
randomized. Exact 95% confidence intervals for the response rate in each treatment arm will be 
calculated. Best overall response (BOR), determined from the sequence of cycle responses 
assessed, will be used for analysis purposes. Response rates will be compared between treatment 
groups using a Pearson Chi-square test and Wald 95% CI will be reported.  
 
Disease Control Rate (DCR): The DCR will be estimated by dividing the total number of 
confirmed CRs, PRs and stable disease (SD) by the total number of patients randomized. DCR 


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will be analyzed as described for RR. Best overall response (BOR), will be used for DCR 
analysis. Proportion of response category by group along with 95% CI will be reported.  
 
Inferential analysis for the secondary endpoints, without multiplicity correction, will be carried 
out for stratification variables (age, prior therapy, ECOG performance status, KRAS mutation 
status, Regorafenib and bevacizumab failure status), One-way ANOVA, and Fisher’s exact tests 
will be used to compare differences across stratification groups. Proportion by group along with 
95% CI will be reported.  
 
A two-tailed p value of <0.05 will be considered statistically significant for all secondary 
endpoints. SAS 9.2 or higher (SAS Institute Inc., Cary, NC) will be used for statistical analysis. 
 
 
 


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11. STUDY MANAGEMENT AND ADMINISTRATION 
 
11.1 ETHICAL CONDUCT OF STUDY (GCP) 
 
The guidelines of the World Medical Association Declaration of Helsinki in its revised edition 
(48th General Assembly, Somerset West, Republic of South Africa, October 1996), the guidelines 
of ICH GCP (CPMP/ICH/135/95), as well as the demands of national drug and data protection 
laws and other applicable regulatory requirements, will be strictly followed. Approval will be 
obtained from the appropriate regulatory authorities before sites are initiated.  
 
11.2 IRB AND ETHICS COMMITTEE APPROVAL  
 
Prior to initiation of the study, the protocol, the informed consent form, the subject information 
sheet(s), details of the subject recruitment procedures and any other relevant study documentation 
will be submitted to the responsible IRB or Ethics Committee (EC). The Investigator will report 
promptly to the IRB/EC any new information that may adversely affect the safety of subjects or 
the conduct of the study. Similarly, the Investigator will submit written summaries of the study 
status to the IRB/EC annually, or more frequently if requested by the IRB/EC. Upon completion 
of the study, the Investigator will provide the IRB/EC with a brief report of the outcome of the 
study, if required. 
 
11.3 PROTOCOL MODIFICATIONS  
 
Modifications of the signed protocol are only possible by approved protocol amendments and 
with the agreement of all responsible persons. The procedure for approval of a protocol 
amendment is identical to that for approval of the protocol. The IRB/EC must be informed of all 
protocol amendments and should be asked for its opinion as to whether a full re-evaluation of the 
ethical aspects of the study is necessary by the committee. This should be fully documented. The 
Investigator must not implement any deviation from or change to the protocol, without discussion 
with, and agreement by, the study Sponsor and prior review and documented approval/favorable 
opinion of the amendment from the relevant IRB/EC, except where it is necessary to eliminate an 
immediate hazard to study subjects, or where the change(s) involves only logistical or 
administrative aspects of the study (e.g., change in CRA(s), change of telephone number(s)). 
Protocol amendments will be submitted to the appropriate authority(ies) as required by the 
applicable regulatory requirement(s). 
 
11.4 SUBJECT INFORMATION AND CONSENT  
 
The Investigator is responsible for ensuring that no subject will receive any study-related 
examination or activity before that subject has given an IRB/EC approved informed consent. The 
subject must give written consent after the receipt of detailed information. The verbal explanation 
will cover all the elements specified in the written information provided for the subject. The 
Investigator will inform the subject of the aims, methods, anticipated benefits and potential 
hazards of the study, including any discomfort it may entail. The subject must be given every 
opportunity to clarify any points he/she does not understand and if necessary, ask for more 
information. At the end of the interview, the subject may be given time to reflect if this is 
required, or if the subject requests more time. Subjects and/or legal guardian forms will be kept 
and archived by the Investigator in the Investigator's study file. It should be emphasized that the 
subject is at liberty to withdraw their consent to participate at any time, without penalty or loss of 


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benefits to which the subject is otherwise entitled. Subjects who refuse to give, or withdraw, 
written informed consent may not be included or continued in this study, but this will not impact 
their subsequent care. The Investigator will notify in writing each subject’s primary care 
physician (or equivalent) of the subject’s intent to participate in the study. 
 
11.5 DATA PROTECTION AND CONFIDENTIALITY  
 
In signing the final protocol, every participating Investigator agrees to keep all information and 
results concerning the study and the investigational product confidential. The confidentiality 
obligation applies to all personnel involved at the investigational site. The Investigator must 
ensure that each participant’s anonymity will be maintained in accordance with applicable laws. 
On eCRFs or other documents submitted to the Sponsor, subjects should not be identified by their 
name, but by subject ID number. The Investigator should keep a separate log of ID numbers, 
names and addresses. Documents that contain the names associated with these ID numbers (e.g. 
written consent/assent forms), are not for submission to the Sponsor and should be maintained by 
the Investigator in strict confidence except to the extent necessary to allow auditing by regulatory 
authorities, auditing or monitoring by the Institutional Review Board/EC, the Sponsor personnel 
or their affiliates and designees (such as CRAs).  
 
Copies of radiological scans and autopsy reports (and other documents) that may be requested by 
the Sponsor should be de-identified. The Investigator shall obtain all such permissions and 
authorizations as may be necessary or desirable to allow the collection and use of information 
protected under federal privacy laws and state privacy laws, including permission/authorization 
for monitoring and analysis (including re-analysis in combination with results of other studies), 
for regulatory submission purposes and for applicable reporting (if any) required to be made by 
Sponsor, its affiliates and their designee.  
 
11.6 STUDY REPORT AND PUBLICATIONS  
 
A final integrated clinical/statistical report will be prepared that is compliant with the ICH 
Harmonized Tripartite Guideline: Structure and Content of Clinical Study Reports 
(CPMP/ICH/137/95). The results of this study will be published and/or presented at scientific 
meetings in a timely manner. The publication policy is described in the contract between the 
Sponsor and Investigator.  
 
11.7 STUDY FILES AND RETENTION OF RECORDS  
 
Copies of all study documents should be retained by the Investigator until at least two years after 
the last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least two years have elapsed since the 
formal discontinuation of clinical development of the investigational product, in accordance with 
21 CFR 312.62. These documents should be retained for a longer period however, if required by 
regulatory requirements or by agreement with the Sponsor. It is the responsibility of the Sponsor 
to inform the Investigator/institution as to when these documents no longer need to be retained. 
The final database will be archived according to the regulatory requirements.  
 
11.8 CASE REPORT FORMS  
 
Data for this protocol will be captured electronically in an Electronic Data Capture (EDC) 
system. Designated study personnel will be provided unique user names and passwords. Each 
study personnel will have specific access within the electronic data collection system based on 


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their role. The EDC system contains an audit trail associated with each individual's unique 
password that will document date and time of data entry and revisions. All protocol-specified data 
is to be entered into the EDC system in a timely manner for review and audit by XBiotech USA, 
Inc. All data is to be entered such that it will allow accurate interpretation and tabulation. It is the 
Investigator's responsibility to ensure that all discontinued orders or changes in study or other 
medications entered into the database correspond to entries in the subject's medical records (i.e. 
source documents) and to acknowledge accurate completion of the eCRF. 
 
11.9 DRUG ACCOUNTABILITY  
 
A Drug Dispensing Log must be kept current and should contain the following information:  
 
• 
Initial inventory upon receipt of supplies at the study site  
• 
Identification number of each subject to whom test drug was administered  
• 
Date(s), quantities, lot numbers and calculations for all test drugs administered  
• 
Final inventory (upon completion of the study) 
 
This inventory must be available for inspection by the Clinical Research Associate. The 
Investigator (or pharmacist, as appropriate) must maintain records of the delivery of the study 
medication to the study site, the inventory at the site, the usage for each subject, and destruction. 
The inventory must be available for monitoring, auditing or inspection. A drug dispensing log 
must be kept current and should contain the following information:  
 
• 
The subject identification number to whom the drug is dispensed  
• 
The lot number of the drug dispensed  
• 
The date(s) and the quantity of the drug dispensed to the subject 
 
11.10 INSPECTIONS  
 
Investigator sites, the study database and study documentation may be subject to quality 
assurance audits during the course of the study either by the Sponsor or their appointed 
representatives. In addition, regulatory bodies at their discretion may conduct inspections. The 
Investigator shall permit the authorized Sponsor, agents of the Sponsor, and regulatory agency 
employees to enter and inspect any site where the drug or records pertaining to the drug are held, 
and to inspect all records relating to an investigation, including subject records. The Sponsor will 
not, however, copy any source data from the patient’s dossier. Completed eCRFs must be made 
available by the Investigator for review by the Sponsor, agents of the Sponsor, the CRA and the 
regulatory agencies. To ensure the accuracy of data submitted, it is mandatory that representatives 
of the Sponsor and of the regulatory agencies have direct access to source documents (e.g. subject 
medical records, charts, laboratory reports, etc.). Subject confidentiality will be protected at all 
times.  
 
11.11 ACCESS TO INFORMATION FOR MONITORING  
 
CRAs will establish and maintain regular contact between the Investigator and the Sponsor. 
CRAs will evaluate the competence of each study center, informing the Sponsor about any 
problems relating to facilities, technical equipment or medical staff. During the study, CRAs will 
check that written informed consent has been obtained from all subjects correctly and that data 
are recorded correctly and completely. CRAs are also entitled to compare entries in eCRFs with 
corresponding source data and to inform the Investigator of any errors or omissions. CRAs will 


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CONFIDENTIAL                                        05 June, 2017                                            PAGE 68 of 74 
 
also monitor adherence to the protocol at the Investigator site. They will arrange for the supply of 
investigational product and ensure appropriate storage conditions are maintained. The CRA will 
make written reports to the Sponsor on each occasion when contact with the Investigator is made, 
regardless of whether it is by phone or in person. During monitoring visits, entries in the eCRFs 
will be compared with the original source documents. The Investigator must agree to meet with 
the CRA at regular intervals and to cooperate in resolving any queries or findings made during 
the monitoring process.  
 
11.12 STUDY DISCONTINUATION  
 
If the study is prematurely terminated or suspended, the Sponsor will promptly inform the 
Investigators/institutions and the regulatory authority(ies) of the termination or suspension and 
the reason(s) for the termination or suspension. The IRB/EC will also be promptly informed and 
provided with the reason(s) for the termination or suspension by the Sponsor or by the 
Investigator/institution, as specified by the applicable regulatory requirement(s). 


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APPENDIX A 
 
 
 
 
Eastern Cooperative Oncology Group (ECOG) Grades 
Grade 
ECOG 
0 
Fully Active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light housework, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities.  
Up and about more than 50% of waking hours. 
3 
Capable of only limited self care, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
5 
Dead 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX B  
 
EORTC-QLQ-C30 (version 3) appended 
 


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10 Prado CMM, Baracos VE, McCargar LJ et al. Body composition as an independent determinant of 5-
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14 Almendro V, et al.  The role of MMP7 and its cross-talk with the FAS/FASL system during the acquisition of 
chemoresistance to oxaliplatin. PLoS One. 2009;4(3):e4728. doi: 10.1371/journal.pone.0004728. Epub 2009 
Mar 6. 
15 Zarbock A, et al.  Platelet-neutrophil-interactions: Linking hemostasis and inflammation.  Blood Reviews 
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16 Matsuo et al. Interleukin-1α Secreted by Pancreatic Cancer Cells Promote Angiogenesis and Its 
Therapeutic Implications. Journal of surgical research. 2009; 153: 274-281. 
 
                                                        


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Hypothalamic-Pituitary-Adrenal Axis.  J. Exp. Med.  2011 21; 208(12):  2449-63. 
30 Stone RL, et al.  Paraneoplastic thrombocytosis in ovarian cancer.  N Engl J Med. 2012 Feb 
16;366(7):610-8. doi: 10.1056/NEJMoa1110352. 
31 Jang et al.  Mass spectrometric quantification of neutral and sialylated N-glycans from a recombinant 
therapeutic glycoprotein produced in Chinese hamster ovary cell lines. Anal. Biochem. 386 (2009) 228-
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33 Gallay et al. Characterization and detection of naturally occurring antibodies against IL-1α and IL-1β in 
normal human plasma. Eur Cytokine Network 1991; 2: 329-338. 
34 Müller et al. Autoantibodies to IL-1α  in sera from umbilical cords, children, and adults, and from 
patients with juvenile chronic arthritis. Scand J Rheumatol. 1996; 25 (3): 164-7 
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SAP_001.pdf: 
2012-PT023 SAP Addendum v1.0...............................................................................................................2
PT023V3 SAP V1.1 ......................................................................................................................................6
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Statistical Analysis Plan Addendum  
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Document History 
Version 
Reason(s) for change 
Date 
V1.0 
Original document  
August 18th 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan Addendum  
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2012-PT023 V3.7 
 
This statistical analysis plan (SAP) addendum describes hard-coding decisions for protocol 
2012-PT023, A Phase III Double-blinded, Placebo Controlled Study of Xilonix™ for Improving 
Survival in Metastatic Colorectal Cancer.   This addendum was finalized after the SAP was 
finalized.   
The date of death for the following patients need to be hard-coded in SAS program to derive the 
overall survival endpoint. The detailed rationales for these decisions are described below, and 
these decisions were made while the database was still blinded.   
In general, the issues were isolated into three categories:  Partial Dates, Missing Date of Death, 
and Randomization in Error.   
• For partial dates, ie those that contain month and year, a conservative approach was taken 
and the 1st of the month was imputed in these cases.   
• For missing date of death, the last date of contact with the patient was used as the date of 
death. 
• The EDC assigns a randomization number whenever the randomization option is selected 
on that page.  There were few of these data entry errors (N=6) in the study, and in each 
case the site confirmed the error.  These patients are considered to be screen failures. 
The following cases have confirmed death, but the date of death is missing (unknown): 
• Patient 3301233005, this patient died based on the survival data sheet, but the date of 
death is missing. In study discontinuation data sheet, this patient had an adverse event on 
08Apr2016, which was used as the date of death in the interim analysis dataset.  In the 
survival data sheet, the last available assessment date is 13Jun2016.  As the patient was 
known to be alive at this time, the last available contact date should be used. 
• Patient 3903233019, this patient died based on the survival data sheet, but the date of 
death is missing. In study discontinuation data sheet, this patient had date for "Other" on 
05-09-2016, which was used as the date of death in the interim analysis dataset.  In the 
survival data sheet, the last available assessment date is 29Jun2016 for ECOG 
assessment.  As the patient was known to be alive at this time, the last available contact 
date should be used. 
• Patient 3802233004, this patient died based on the survival data sheet, but the date of 
death is missing. In study discontinuation data sheet, this patient had date for "Removed 
from Study by PI" on 22-Nov-2016.  In the survival data sheet, the last available 
assessment date is 21Mar2017 for ECOG assessment.  As the patient was known to be 
alive at this time, the last available contact date should be used. 
 
 
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2012-PT023 V3.7 
 
The following cases do not need hard-coding, but imputations will be done for partial date of 
death: 
• Patient 3905233015, the death date has missing day part, Mar-2017, this date will be 
imputed as 01-Mar-2017. 
• Patient 3909233001, the death date has missing day part, Feb-2017, this date will be 
imputed as 01-Feb-2017. 
• Patient 3905233011, the death date has missing day part, Jun-2016. In the interim 
analysis dataset, the death date was set as 06-Jun-2016.  After further clarification, this is 
the date that the site completed the discontinuation page in the EDC.  In a query response, 
the site noted that they did not know the exact date of death, but they knew the patient 
died in June of 2016.  As the June 6th date is not the last available contact date with the 
patient, rather the date the site entered discontinuation information, this date should not 
be used.  This case is being classified as a partial date, therefore the date of 01-Jun-2016 
will be imputed. 
• Patient 3909233003, the death date has missing day part, Dec-2016. In the interim 
analysis dataset, the date of death was set as 01-DEC-2016.  This is consistent with the 
decision to use the 1st of the month and therefore 01-DEC -2016 will be used as the date 
of death. 
The following patients were screen failures, however the site erroneously clicked on the 
randomization button in the EDC.  Once this happens, a randomization number is assigned and 
this can’t be undone.  Because these patients did not meet eligibility criteria and the site 
confirmed the error, these patients are not included in the data analysis. 
• 1027233009 
• 3909233006 
• 1025233003 
• 1029233008 
• 1069233002 
• 3301233002 
 
 
 
 
 
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