A Phase 2, Single Arm, Two Period Study of Sodium Cridanimod in Conjunction With Progestin Therapy in Patients With Endometrial Carcinoma
Phase: PHASE2
Conditions: Endometrial Cancer
Sponsor: Xenetic Biosciences, Inc.

Protocol No. VX-EC-2-02 
Xenetic Biosciences, Inc. 
Page 1 of 67 
Version 6.0, 2Jan2018 
Confidential 
A Phase 2, Single Arm, Two Period Study of Sodium Cridanimod 
in Conjunction with Progestin Therapy in Patients  
with Endometrial Carcinoma 
Protocol Number: 
VX-EC-2-02 
Development Phase: 
Phase 2 
Investigational Product: 
Sodium Cridanimod 
IND Number: 
131625 
EudraCT Number: 
TBD 
Protocol Version: 
Final 6.0 
Protocol Date: 
02 January 2018 
Sponsor: 
Xenetic Biosciences, Inc.  
99 Hayden Avenue, Suite 230 
Lexington, MA 02421 
Confidentiality Statement 
The document contains confidential and proprietary information and is the property of Xenetic Biosciences, Inc.  The 
information may be provided only to Investigators, appropriate trial personnel, members of the Institutional Review 
Board/Independent Ethics Committee, and personnel of the authorities to whom it is submitted.  This protocol may 
not be photocopied or discussed with third parties without prior written authorization from Xenetic Biosciences, Inc. 
NCT# 03077698

 
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Table of Contents 
SIGNATURE PAGE (SPONSOR)···················································································· 7
SIGNATURE PAGE (INVESTIGATOR)············································································· 8
LIST OF ABBREVIATIONS AND KEY TERMS ··································································· 9
SYNOPSIS ··············································································································· 11
STUDY DESIGN AND ASSESSMENT SCHEDULE ·························································· 18
1.
INTRODUCTION ································································································ 23
1.1.Background ································································································ 23
1.1.1. Endometrial Cancer ············································································ 23
1.1.2. Progestins for the Treatment of Endometrial Cancer ·································· 23
1.2.Sodium Cridanimod ····················································································· 24
1.2.1. Nonclinical Data Relevant to Endometrial Cancer ····································· 24
1.2.2. Clinical Data Relevant to Endometrial Cancer ·········································· 24
1.3.Summary of Key Safety Information for Study Drug ········································· 25
1.3.1
Adverse Reactions Reported with Megestrol Acetate ································· 26
1.3.2
Adverse Reactions Reported with Lidocaine Hydrochloride ························· 26
1.4Rationale for Study ······················································································· 27
1.5.Rationale for Study Population, Exclusion Criteria ··········································· 27
1.6.Rationale for Selection of Dose of Study Drug ················································· 28
1.7.Rationale for Treatment Duration ··································································· 28
2.
STUDY OBJECTIVE(S), DESIGN AND ENDPOINTS ················································· 29
2.1.Study Objectives ························································································· 29
2.1.1. Primary Objective··············································································· 29
2.1.2. Secondary Objective ··········································································· 29
2.1.3. Translational Research Objective ·························································· 29
2.2.Study Design······························································································· 29
2.2.1 Treatment Period 1 (Progestin Monotherapy): ············································· 29
2.2.2 Treatment Period 2 (Combination Therapy): ··············································· 30
2.2.3 Follow-up Period: ················································································· 31
2.3.Endpoints ··································································································· 31
2.3.1. Primary Endpoint ··············································································· 31
2.3.2. Secondary Endpoints ·········································································· 31
3.
STUDY POPULATION ························································································· 31
3.1.Selection of Study Population ······································································· 31
3.2.Informed Consent ························································································ 31
3.3.Screening ··································································································· 32

 
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3.4.Inclusion Criteria ························································································· 32
3.5.Exclusion Criteria ························································································ 33
3.6.Discontinuation Criteria for Individual Subjects ··············································· 33
3.7.Patient Requirements ··················································································· 34
3.8.Subject Identification ··················································································· 34
4.
STUDY DRUG ··································································································· 34
4.1.Description of Study Drugs ··········································································· 34
4.1.1 Sodium Cridanimod ·············································································· 34
4.1.2 Megestrol acetate ················································································· 34
4.1.3 Lidocaine Hydrochloride ········································································ 34
4.2.Preparation of Sodium Cridanimod ································································ 34
4.3.Study Drug Handling ···················································································· 35
5.
TREATMENTS AND EVALUATION ········································································· 35
5.1.Dosing and Administration of Study Drugs and Other Medications ····················· 35
5.1.1. Dose/Dose Regimen and Administration ················································· 35
 
5.1.1.1   Megestrol acetate ··································································· 35
 
5.1.1.2   Sodium Cridanimod ································································ 35
5.1.2. Dose Modifications ············································································· 36
5.1.3. Duration of Therapy ············································································ 36
 
5.1.3.1Treatment Period 1 ································································· 36
 
5.1.3.2  Treatment Period 2 ·································································· 36
5.1.4. Duration of Follow-up ·········································································· 36
5.1.5. Subject Compliance ············································································ 37
5.2.Demographics and Baseline Characteristics ··················································· 37
5.2.1. Demographics ··················································································· 37
5.2.2. Medical History ·················································································· 37
5.3.Assessment of PrR Status at Screening ·························································· 37
5.4.Visit Schedule and Required Study Procedures ··············································· 37
5.4.1. Screening ························································································· 37
5.4.2. Treatment ························································································· 38
5.4.3. Follow-up Period ················································································ 44
5.5.Efficacy Assessments ·················································································· 45
5.5.1. Visual Tumor Examination ···································································· 45
5.5.2. Tumor Imaging and Measurement (CT/MRI) ············································ 45
5.5.3. Gynecologic Oncology Group (GOG) Performance Status ·························· 45

 
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5.6.Assessment of Response ············································································· 46
5.6.1. Measurable Disease Definitions ···························································· 46
5.6.2. Definitions of Response ······································································· 47
5.6.3. Evaluations of a Subject’s Best Overall Response ····································· 48
5.7.Safety Assessments ····················································································· 49
5.7.1. Concomitant Medication ······································································ 49
5.7.2. Vital Signs ························································································ 50
5.7.3. Laboratory Assessments ····································································· 50
 
5.7.3.1.Hematology ············································································ 50
 
5.7.3.2.Serum Chemistry ····································································· 50
 
5.7.3.3.Urinalysis ··············································································· 51
5.7.4. Pregnancy Test ················································································· 51
5.7.5. Physical Examination ·········································································· 51
5.7.6. Electrocardiogram ·············································································· 51
5.7.7. Patient Diary ····················································································· 52
5.8.Optional Sub-Study Procedures ····································································· 52
5.8.1. Optional Pharmacokinetic (PK) Sub-Study ··············································· 52
5.9.Adverse Events and Other Safety Aspects ······················································ 52
5.9.1. Definition of Adverse Events ································································· 52
5.9.2. Definition of Serious Adverse Events ······················································ 54
5.9.3. Criteria for Causal Relationship ····························································· 55
5.9.4. Criteria for Defining the Severity of an Adverse Event ································ 55
5.9.5. Reporting of Serious Adverse Events (SAEs) ··········································· 55
5.9.6. Reporting of Deaths ············································································ 56
5.9.7. Procedure in Case of Pregnancy ··························································· 56
6.
TERMINATION OF THE CLINICAL STUDY ······························································ 56
7.
STATISTICAL METHODOLOGY ············································································ 57
7.1.Sample Size ································································································ 57
7.2.Analysis Sets ······························································································ 57
7.2.1. Safety Population ··············································································· 57
7.2.2. Full Analysis Set (FAS) ········································································ 57
7.2.3. Per Protocol Set (PPS) ········································································ 57
7.3.Demographics and Other Baseline Characteristics ··········································· 58
7.4.Analysis of Efficacy ····················································································· 58
7.4.1. Analysis of Primary Objective ······························································· 58
7.4.2. Analysis of Secondary and Translational Objectives ·································· 58

 
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7.5.Analysis of Safety ························································································ 59
7.5.1. Adverse Events ················································································· 59
7.5.2. Clinical Laboratory Evaluations ····························································· 59
7.5.3. Physical Examination ·········································································· 59
7.5.4. Vital Signs ························································································ 59
7.5.5. Electrocardiogram ·············································································· 59
7.5.6. Gynecologic Oncology Group (GOG) ····················································· 60
7.6.Analysis of Pharmacokinetics ······································································· 60
7.7.Protocol Deviations ······················································································ 60
7.8.Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········· 60
7.8.1. Missing Data ····················································································· 60
7.8.2. Visit Windows ···················································································· 61
8.
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS ······································ 61
8.1.Procedure for Clinical Study Quality Control ··················································· 61
8.1.1. Clinical Study Monitoring ····································································· 61
8.1.2. Source Data ····················································································· 61
8.1.3. Language ························································································· 61
8.1.4. Data Collection ·················································································· 61
8.1.5. Data Management·············································································· 62
8.1.6. Protocol Deviations ············································································ 62
8.1.7. End of Trial ······················································································· 63
8.2.Ethics and Protection of Subject Confidentiality ·············································· 63
8.2.1. Independent Ethics Committee / Institutional Review Board (IRB) / Competent 
Authorities (CA) ········································································ 63
8.2.2. Ethical Conduct of the Study ································································ 63
8.2.3. Informed Consent of Subjects ······························································· 63
8.2.4. Subject Confidentiality ········································································· 64
8.2.5. Financial Disclosure of Investigators ······················································ 64
8.3.Administrative Matters ················································································· 64
8.3.1. Arrangement for Use of Information and Publication of the Clinical Study ······· 64
8.3.2. Regulatory Authority Approval ······························································· 65
8.3.3. Protocol Amendment and/or Revision ····················································· 65
8.3.4. Study Documentation and Storage························································· 65
8.3.5. Signatory Investigator for Clinical Study Report ········································ 65
9.
QUALITY ASSURANCE ······················································································· 66
10. STUDY ORGANIZATION······················································································ 66

 
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10.1.Data and Safety Monitoring Board ································································ 66
11. REFERENCES ·································································································· 67
 
Appendix 1: New Response Evaluation Criteria in Solid Tumours: Revised RECIST Guideline (version 1.1) 
 

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SIGNATURE PAGE (SPONSOR) 
A Phase 2, Single Arm, Two Period Study of Sodium Cridanimod in Conjunction with Progestin 
Therapy in Patients with Endometrial Carcinoma 
Protocol No. VX-EC-2-02 
The signature below constitutes the approval of this protocol by the signatory and provides the necessary 
assurances that this study will be conducted according to all stipulations of the protocol, including all state-
ments regarding confidentiality. 
Signed: 
___________________________________________ 
Curtis Lockshin, PhD 
Chief Scientific Officer 
Xenetic Biosciences, Inc. 
Date: 
_____________________ 
02 Jan 2018

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SIGNATURE PAGE (INVESTIGATOR) 
A Phase 2, Single Arm, Two Period Study of Sodium Cridanimod in Conjunction with Progestin 
Therapy in Patients with Endometrial Carcinoma 
Protocol No. VX-EC-2-02 
The signature below constitutes acknowledgement of my review of this protocol as well as an agreement to 
abide by its terms and conditions set out herein. 
I agree to recruit and treat patients in an ethical manner and conduct this trial strictly according to the 
protocol, applicable regulations and current Good Clinical Practices.   
I have received an Investigator’s Brochure for Sodium Cridanimod and have been informed about the 
pharmacology, toxicology and clinical findings related to the administration of this Investigational 
Medicinal Product (IMP).   
I will ensure all Sub-Investigators and research personnel involved in this trial, will understand 
information regarding the IMP as well as the protocol and will conduct the trial in the manner described 
above. 
Principal Investigator: 
Signature: 
Printed Name: 
Date 
Address: 

 
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LIST OF ABBREVIATIONS AND KEY TERMS 
Abbreviation 
Term 
AE 
Adverse event 
ALT 
Alanine transaminase 
APrR 
Activated progesterone receptor 
AST 
Aspartate transaminase 
ß-hCG 
Beta-human chorionic gonadotropin 
BUN 
Blood urea nitrogen 
CI 
Confidence interval 
eGFR 
Estimated Glomerular filtration rate 
CR 
Complete response 
eCRF 
Electronic Case Report Form 
CRO 
Contract Research Organization 
CT 
Computed tomography 
dL 
Deciliter 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram, also Electrocardiography 
EOS 
End of Study 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
GOG 
Gynecologic Oncology Group 
ICH 
International Conference on Harmonisation 
IHC 
Immunohistochemistry 
IEC 
Independent Ethics Committee 
i.m. 
Intramuscularly 
IMP 
Investigational medicinal product 
IRB 
Institutional Review Board 
kg 
Kilogram 
LDH 
Lactate dehydrogenase 
MA 
megestrol acetate 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
mg 
Milligram 
mL 
Milliliter 
MPA 
Medroxyprogesterone acetate 
MRI 
Magnetic resonance imaging 
NA 
Not applicable 

 
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Abbreviation 
Term 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
ODCR 
Overall Disease Control Rate 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PCR 
Polymerase chain reaction 
PD 
Progressive disease 
PFS 
Progression-free survival 
p.o. 
Per os (per mouth) 
PR 
Partial response 
PrR 
Progesterone receptor 
QTcB 
QT ECG interval corrected for heart rate according to Bazett's formula  
QTcF 
QT ECG interval corrected for heart rate according to Fridericia’s  formula 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SD 
Stable disease 
SFU 
Safety Follow-up Visit 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SOP 
Standard operating procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TP1 
Treatment Period 1 
TP1-EXT 
Treatment Period 1 Extension 
TP2 
Treatment Period 2 
ULN 
Upper limit of normal 
 

 
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  SYNOPSIS 
Investigational  
Medicinal Product 
Sodium Cridanimod 125 mg/mL 
Study Title 
A Phase 2, Single Arm, Two Period Study of Sodium Cridanimod in 
Conjunction with Progestin Therapy in Patients with Endometrial Carcinoma 
Study Code 
VX-EC-2-02 
Phase 
2 
Study Duration 
Subjects determined to have progesterone receptor (PrR) positive status 
from an archival tumor tissue sample at Screening will participate in 
Treatment Period 1 receiving megestrol acetate (progestin monotherapy) for 
up to 24 weeks.  Subjects determined to have disease progression within 
the 24 weeks of Treatment Period 1 will qualify to participate in Treatment 
Period 2.  Subjects determined to continue to have disease control after 24 
weeks of treatment will not be eligible for Treatment Period 2, and will return 
for an End of Study Visit within 2 weeks and be discontinued from the study. 
Subjects determined to have PrR negative status from an archival tumor 
tissue sample at Screening will enroll directly into Treatment Period 2 and 
will receive combination treatment (Sodium Cridanimod and megestrol 
acetate) until documented disease progression. Once disease progression 
is documented in Treatment Period 2, subjects will return for the Safety 
Follow-up Visit four (4) weeks following the last treatment and then continue 
to be followed for an additional 12-month period for overall survival.   
Considering the estimated accrual rate of 4-6 subjects per month, the total 
duration of the study after the first visit of the first subject is about 36 
months. 
Study Objectives 
Primary Objective: 
To assess the antitumor activity of Sodium Cridanimod in conjunction with 
progestin therapy as measured by Overall Disease Control Rate (ODCR) in 
women with recurrent or persistent endometrial carcinoma not amenable to 
surgical treatment or radiotherapy who have either failed progestin 
monotherapy or who have been identified as PrR negative. 
Secondary Objectives: 
Efficacy: To assess Objective Response Rate (ORR), including partial 
response (PR) and complete response (CR), Progression-free Survival 
(PFS), Duration of Stable Disease (SD) and Overall Survival (OS) for 
subjects receiving Sodium Cridanimod, in conjunction with progestin 
therapy. 
Safety: To evaluate the safety and tolerability of Sodium Cridanimod, 
possibly in conjunction with progestin therapy, as measured by adverse 
events, laboratory safety parameters, and cardiac safety assessments 
(including QT prolongation potential).  
Translational Objective: To assess pharmacokinetics data of Sodium 
Cridanimod and megestrol acetate after a single dose and after multiple 

 
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dose administrations and possible pharmaceutical interaction between 
Sodium Cridanimod and megestrol acetate. 
Study Design 
This is an open-label, multi-center, single-arm, two-period Phase 2 study. 
The study will investigate the efficacy of Sodium Cridanimod in conjunction 
with progestin therapy in a population of subjects with endometrial cancer 
who have failed progestin monotherapy or who have been identified as PrR 
negative. 
All patients must have endometrial cancer PrR status determined from an 
archival sample at Screening.  The PrR status (positive or negative) will be 
determined by central laboratory by IHC testing.  
There are two treatment periods and a follow-up period within the study.  
Treatment Period 1 (Progestin Monotherapy):  During Treatment Period 
1, all eligible subjects determined to be PrR positive will receive progestin 
monotherapy (megestrol acetate 160 mg p.o. / day) for up to 24 weeks.  
Subjects will have a CT or MRI scan after 12 and 24 weeks of progestin 
monotherapy, with response to treatment being assessed according to 
RECIST 1.1 criteria. Subjects determined to have disease progression will 
qualify to enroll into Treatment Period 2. 
Subjects determined to have disease control (SD, PR or CR) by tumor 
assessment after 24 weeks in Treatment Period 1, will be ineligible to enter 
Treatment Period 2.  The subject will be withdrawn from the study treatment 
and return for the End of Study Visit within 2 weeks to be discontinued from 
the study. 
Subjects withdrawn from Treatment Period 1 will be treated in accordance 
with local standards and clinical practice (which may include continuation of 
progestin therapy).  A subject may be discontinued from Treatment Period 1 
at any time if the subject experiences a change in symptoms and/or if 
disease progression is suspected by the Investigator.  
• 
Subjects who discontinue Treatment Period 1 prematurely (receiving 
< 4 weeks of progestin monotherapy) for any reason, will be excluded 
from the remainder of the study. 
Subjects determined to be PrR negative at Screening will not enroll into 
Treatment Period 1. These subjects will enroll directly into Treatment Period 
2 (Visit 1, Day 0). 
Treatment Period 2 (Combination Treatment):  All subjects determined to 
be PrR negative at Screening and those who received at least 4 weeks of 
progestin monotherapy and who experienced disease progression during 
Treatment Period 1 will enter Treatment Period 2 of the study (Visit 1, Day 
0).  
During Treatment Period 2, subjects will receive Sodium Cridanimod (500 
mg, 2 times / week, intramuscularly) in combination with continued 
progestin treatment (megestrol acetate 160 mg p.o. / day).  

 
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• 
For those subjects who participated in Treatment Period 1, there 
should be no interruption of progestin therapy between Treatment 
Period 1 and Treatment Period 2.  
• 
Subjects will receive combination treatment until disease progression 
as defined according to RECIST 1.1 criteria, with response 
assessments performed at 12-week intervals.  
• 
Confirmation of objective responses in Treatment Period 2 will be 
performed at least 4 weeks after the criteria for response are first met. 
Follow-up Period: Once subjects progress during Treatment Period 2, they 
will return for the Safety Follow-up Visit four (4) weeks following the last 
treatment, and then continue to be followed for an additional 12-month 
period for overall survival. 
Study Population 
A total of 72 women with recurrent or persistent endometrial cancer not 
amenable to surgical treatment or radiotherapy but suitable to be treated 
with progestins will be enrolled in the study. 
Eligibility Criteria 
Inclusion Criteria 
1. Female patients 18 years of age or older; 
2. Histologically confirmed serous carcinoma or endometrioid type of 
endometrial carcinoma (histological documentation of recurrence is 
not required); 
3. Recurrent or persistent progressive disease which is refractory to 
curative therapy or established treatments and cannot be treated 
with surgery or radiotherapy; 
4. Measurable disease, as defined by RECIST 1.1 criteria; 
5. At least one “target lesion” to be used to assess response, as 
defined by RECIST 1.1 criteria. Tumors within a previously 
irradiated field will be designated as “non-target” lesions unless 
previous progression is documented; 
6. Availability of archived tumor tissue sample that can be used for 
assessment of PrR status by the central laboratory; 
7. GOG performance status 0-2 (refer to Table 9 under Section 5.5.3); 
8. Estimated Glomerular filtration rate ≥ 50 mL/min; 
9. Total bilirubin ≤ 2.5 times upper limit of normal (ULN); 
10. AST ≤ 2.5 times ULN (≤ 5 times ULN for patients with liver 
metastases); 
11. Alkaline phosphatase ≤ 2.5 times ULN (≤ 5 times ULN for patients 
with liver metastases); 
12. Albumin ≥ 3.0 mg/dL; 
13. Ability to take oral medication; 
14. Patients able to understand the nature of the study and who are 
willing to give written informed consent; 

 
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15. And for Treatment Period 2 only: 1) Patients participating in 
Treatment Period 1 must have had disease progression after 
receiving at least 4 weeks of progestin therapy or 2) Patients must 
be determined as PrR negative status at Screening.   
Exclusion Criteria 
1. Mixed histology of the tumor or evidence of tumor histology other 
than serous carcinoma or endometrioid type of endometrial 
carcinoma; 
2. Concurrent systemic corticosteroid therapy; 
3. Concurrent oral contraceptive use / Women of childbearing 
potential not using highly effective means of contraception; 
4. Pregnancy confirmed by pregnancy test / Lactating women (for 
women of childbearing potential); 
5. Prior therapy with hormonal progestin agents; 
6. Patients who are candidates for treatment with standard 
chemotherapy agents (there is no limit to the number of lines of 
prior chemotherapy); 
7. History of blood clot; 
8. History of known bleeding disorder (i.e. disseminated intravascular 
coagulation or clotting factor deficiency); 
9. Major surgery within 4 weeks prior to the start of the study; 
10. Patients with clinically significant illnesses which, according to the 
Investigator, could compromise participation in the study; 
11. History of other clinically active malignancies within 5 years, except 
for carcinoma in situ of the cervix, basal cell carcinoma, or 
squamous carcinoma of the skin. 
12. Known hypersensitivity or idiosyncratic reaction to any of the study 
drugs (Sodium Cridanimod, megestrol acetate, lidocaine) and 
excipients; 
13. Patients with known brain metastases; 
14. Patients currently receiving any other investigational agents; 
15. Patients currently receiving any other anticancer therapies; 
16. Participation in any other clinical study within the last 4 weeks prior 
to the start of the study; 
Treatment 
During Treatment Period 1, subjects who are PrR positive will receive 
megestrol acetate only.  Megestrol acetate will be taken p.o. in a total daily 
dose of 160 mg.   
Subjects who are PrR negative will not participate in Treatment Period 1, 
but instead enroll directly into Treatment Period 2. 
During Treatment Period 2, subjects will receive megestrol acetate in 
combination with Sodium Cridanimod.   
• Megestrol acetate will be taken p.o. in a total daily dose of 160 mg.   

 
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• Sodium Cridanimod (500 mg / 4 mL) is to be diluted with 1 mL of 2% 
lidocaine hydrochloride (5 mL total) and administered twice a week 
intramuscularly.  
For Sodium Cridanimod doses that do not correspond to a Study Visit, the 
drug may be administered either at the clinical site or at home by a medical 
service provider if feasible.   
Subjects will be provided a diary and instructed to record all doses of 
megestrol acetate. 
Efficacy Assessments 
A disease or tumor assessment will be performed by clinical examination 
for palpable or visual tumor lesions as well as by computerized 
tomography (CT) or magnetic resonance imaging (MRI).  
A CT or MRI scan with tumor assessments will be performed during 
Screening (baseline). 
During Treatment Period 1, a CT or MRI scan and tumor assessments will 
be performed following 12 weeks of treatment (at Visit -1), and again after 
24 weeks of treatment (at Visit TP1-EXT) if the subject achieved disease 
control at the 12 Week scan. 
During Treatment Period 2, CT or MRI scans and tumor assessments will 
be performed every 12 weeks.   
RECIST 1.1 criteria will be used to interpret all scans.  
During Treatment Period 2, all objective responses must be confirmed with 
an additional scan performed at least four weeks after the criteria for 
response were initially met.  
For evaluating subject responses during Treatment Period 2, the 
measurements for determining progression in Treatment Period 1 will be 
used as the new baseline measurements. 
Safety Assessments 
Physical examinations, ECGs, adverse events and clinical laboratory 
assessments will be monitored.  All laboratory testing for safety will be 
conducted by local laboratories. 
An independent Data and Safety Monitoring Board (DSMB) will monitor the 
study. 
Electrocardiograms 
(ECG) 
An ECG will be obtained during Screening. 
During Treatment Period 1, at Study Visit -3, an ECG will be obtained prior 
to first dose of megestrol acetate.  An ECG will be obtained at each of the 
remaining study visits (prior to drug administration of megestrol acetate 
whenever possible).  An ECG will be obtained at the End of Study Visit. 
During Treatment Period 2, at Study Visits 1 and 3, an ECG will be obtained 
5 times: before administration of Sodium Cridanimod, and at 15, 60, 120 
and 360 (±5) minutes after administration to evaluate study drug-induced 
QT prolongation potential.  At all other study visits during Treatment Period 
2, only one ECG will be obtained prior to Sodium Cridanimod 
administration.  An ECG will be obtained at the Safety Follow-up Visit. 
Optional 
Pharmacokinetic (PK) 
Sub-Study 
An important objective of this study is to investigate the pharmacokinetics of 
megestrol acetate when administered alone (Treatment Period 1), and the 

 
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possible pharmacokinetic drug-drug interactions of Sodium Cridanimod and 
megestrol acetate when administered together.  
For subjects who have consented to participate in the Pharmacokinetics 
(PK) Sub-Study, additional blood samples will be taken as follows: 
• Treatment Period 1 (at 10 timepoints):  Study Visit -3, before 
administration of megestrol acetate, and 1, 2, 3, 4, 6, 24, 48, 72 and 96 
hours after first administration of megestrol acetate. Subjects who are 
PrR negative will not participate in this portion of the PK Sub-Study. 
• Treatment Period 2 (at 15 timepoints): Study Visit 1, before 
administration of the study drugs and at 15, 30, 45, 60 and 90 minutes, 2, 
3, 4 and 6 hours after administration. Blood samples will additionally be 
taken on Days 3, 7, 10, 56 (Visit 3) and 84 (Visit 4) of Treatment Period 2 
prior to the administration of both Sodium Cridanimod and megestrol 
acetate.  
Blood samples will be analyzed at a central laboratory. 
Efficacy Endpoints 
1. 
Overall Disease Control Rate (ODCR) including SD, PR and CR, as 
defined by RECIST 1.1 criteria 
2. 
Objective Response Rate (ORR) including CR and PR, as defined 
by RECIST 1.1 criteria 
3. 
Progression-free survival (PFS) 
4. 
Duration of Stable Disease (SD) 
5. 
Overall survival (OS)
Statistics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sample Size: The primary objective of the study is to evaluate the efficacy 
of the study drug by the frequency of subjects with overall disease control 
(including SD, PR, and CR). 
The null hypothesis specifies the probability of a subject experiencing 
disease control to <5%. A clinically significant difference is predefined as a 
15% increase in the probability of the event (i.e., disease control rate of 
20%). Using the Fleming’s single stage procedure (in which a 
predetermined number of patients is recruited to the study and a decision 
about activity is obtained from the number of responses (including SD, PR, 
or CR) amongst these patients) with the probabilities of type I and type II 
errors of 5% (one-sided) and 10%, respectively, approximately 40 subjects 
are planned to be enrolled to Treatment Period 2. It is estimated that 
approximately 20-25% of subjects will be classified as PrR negative and go 
directly into Treatment Period 2.  This group will represent 14-16 of the 
Treatment Period 2 subjects. The rate of subjects who will have progressive 
disease following treatment with megestrol acetate in Treatment Period 1 
and then move on to Treatment Period 2 is estimated at 55-60%.  These 
subjects will represent 30-32 of the Treatment Period 2 subjects 
(Approximately 24-25 subjects treated in Treatment Period 1 will not exhibit 
progressive disease and will not move into Treatment Period 2.)  Estimating 
the rate of subjects who will be unavailable for disease assessment for 
various reasons at 10-15%, it is planned to enroll 72 total subjects. 
Analysis: A descriptive analysis approach will be used to analyze 
demographic and baseline characteristics, as well as safety and efficacy 
data (mean, standard deviation, median, minimum, maximum, range, 

 
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quintiles, number of valid cases for continuous variables and n, frequency 
and percentage for categorical variables with 95% confidence limits, when 
appropriate). 
All subjects who received a full or partial dose of the study drug (in 
Treatment Period 2) on at least one occasion are considered evaluable 
subjects for safety analysis. All treated subjects in Treatment Period 2 who 
also undergo a CT or MRI scan with tumor assessment after 12 weeks, or 
who discontinue treatment prior to 12 weeks solely due to disease 
progression, will be included in the Full Analysis Set (FAS), which will be 
used for the efficacy evaluation.  The Per Protocol population (all FAS 
subjects, excluding those for whom major protocol violations have been 
identified) will be used in the sensitivity analyses for all secondary efficacy 
endpoints. 
The ODCR will be determined as the proportion of treated subjects who 
have achieved SD, PR or CR. The ORR will be determined as the 
proportion of treated subjects who have achieved CR or PR. Estimates of 
the ORR and the ODCR will be presented with the corresponding 95% 
confidence interval. PFS, duration of stable disease, and OS will be 
analyzed using the Kaplan-Meier method. The Kaplan-Meier survival curves 
will be plotted. OS is defined as the time from the first dose of study drug 
(beginning of Treatment Period 2) until the date of death from any cause. 
Subjects who do not die will be censored for this analysis at the last 
documented date at which the subject is known to be alive. PFS is defined 
as the time from the first dose of study drug (beginning of Treatment Period 
2) until objective tumor progression or death. Medians for time to event 
variables will be presented with the corresponding 95% confidence 
intervals. 
Interim Analysis 
Interim analysis will be performed for the primary efficacy endpoint (ODCR) 
once the first tumor assessment during Treatment Period 2 is completed for 
at least 20 enrolled subjects. An interim analysis of all efficacy endpoints 
(with the exclusion of overall survival) may also be performed once all 
enrolled subjects have entered the Follow-up Period and are being followed 
for overall survival. Analysis of all safety endpoints will also be included in 
any interim analyses. 
Number of Study 
Centers (and 
Locations) Planned 
Up to 50 study sites in the US and Europe are planned for enrollment. 
Estimated Time 
Schedule 
First subject enrolled:    September 2017 
Recruitment completed:  September 2018 
Last subject completed the study: January 2021 

 
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STUDY DESIGN AND ASSESSMENT SCHEDULE 
Figure 1:  Study Flow Chart 
 

 
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Table 1:  Screening Schedule of Assessments 
Screening 
Study Calendar (Weeks) 
-18 to -15 
Procedures and Assessments 
Informed consent 
X 
Eligibility Criteria 
X 
Demographics 
X 
Medical History 
X 
Concomitant Medication 
X 
Physical Exam 
X 
Vital Signs 
X 
Height 
X 
Weight 
X 
Performance Status 
X 
CBC w/ diff, platelets 
X 
Serum chemistryA 
X 
eGFR 
X 
Urinalysis 
X 
Serum Pregnancy Test (B-hCG) B 
X 
ECG 
X 
Assessment of Adverse Events 
X 
PrR status of archived tumor tissue determined by central lab 
X 
Imaging (CT/MRI) E 
X 
Tumor Assessment (using RECIST criteria) E 
X 
Footnotes 
A -  Phosphate, sodium, potassium, chloride, calcium, bicarbonate, creatinine, creatine 
kinase, glucose, blood urea nitrogen (BUN), total proteins, albumin, total bilirubin, alkaline 
phosphatase, LDH, SGOT/AST, SGPT/ALT. 
B -  For women of childbearing potential. 
E -  Screening tumor assessments must be performed <10 days before Visit -3. 

 
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Table 2:  TP1 Schedule of Visits and Assessments 
Treatment Period 1 
(PrR Positive Patients Only) 
Subjects Ineligible 
to enter TP2 or who 
Withdraw Early 
     Study Visits 
-3 
-2 
-1 
TP1-EXT 
End of Study (EOS) 
     Study Calendar (Weeks) 
-14 
-8 
-2 
+12 wks 
+ 2 weeks 
                                                        Treatments 
 
Progestin therapy (Megestrol acetate) Dispensing/ReturnF 
D 
R/D 
R/D 
R/D 
R 
                                           Procedures and Assessments 
Eligibility Criteria 
X 
 
 
 
 
Concomitant Medication 
X 
X 
X 
X 
X 
Physical Exam 
XC 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
Weight 
XC 
X 
X 
X 
X 
Performance Status 
XC 
X 
X 
X 
X 
CBC w/ diff, platelets 
XC 
X 
X 
X 
X 
Serum chemistryA 
XC 
X 
X 
X 
X 
eGFR 
XC 
X 
X 
X 
X 
Urinalysis 
 
 
 
 
X 
Urine Pregnancy TestB 
 
 
 
 
X 
ECG 
XH 
XH 
XH 
XH 
X 
Blood Draw (for PK sub-study)G 
XG 
 
 
 
 
Assessment of Adverse Events 
X 
X 
X 
X 
X 
Imaging (CT/MRI) 
 
 
X 
XD 
 
Tumor Assessment (using RECIST criteria) 
 
 
X 
XD 
 
Patient Diary Issue/CollectionF 
I 
I/C 
I/C 
I/C 
C 
Subject Compliance 
 
X 
X 
X 
X 
Footnotes 
A -  Phosphate, sodium, potassium, chloride, calcium, bicarbonate, creatinine, creatine kinase, glucose, blood urea nitrogen (BUN), total proteins, albumin, total bilirubin, 
alkaline phosphatase, LDH, SGOT/AST, SGPT/ALT. 
B -  For women of childbearing potential. 
C -  These assessments on Visit -3 are only performed if more than 7 days have passed since the previous evaluation at Screening. 
D -  The tumor assessments near the conclusion of Treatment Period 1 are scheduled to take place within 2 weeks prior to TP1 EOS Visit or TP2 Visit 1 (Day 0) so as to allow 
adequate time to obtain tumor measurements prior to Treatment Period 2. This 2 week window can be shortened (and Visit 1 may occur) as soon as these tumor 
measurements are available. 
F -  D = Dispense, R = Return, I = Issue, C = Collect 
G - For subjects who consent to participate in the PK sub-study, blood samples are taken before administration of megestrol acetate as well as 1, 2, 3, 4, 6, 24, 48, 72 and 96 
hours after first administration of megestrol acetate during Visit -3. 
H – ECGs to be performed prior to study drug administration whenever possible.  Exception:  ECG performed at End of Study Visit. 

 
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Table 3:  TP2 Schedule of Visits and Assessments 
Treatment Period 2 
Study Visits 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 - ? 
Safety 
Follow-up 
VisitG 
Follow Up 
Period- OS
Study Calendar 
(Weeks) 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48, 60 
etc.F 
 
 
Treatments 
Sodium 
Cridanimod 
Sodium Cridanimod is administered twice a week on either Mondays and Thursdays or  
Tuesdays and Fridays for the duration of Treatment Period 2. 
 
 
Progestin therapy 
(Megestrol acetate) 
Dispensing/ReturnJ 
R/D 
R/D 
R/D 
R/D 
R/D 
R/D 
R/D 
R/D 
R/D 
R/D 
R/D 
R/D 
R/DH 
R 
 
Procedures and Assessments 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical Exam 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Performance 
Status 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
CBC w/ diff, 
platelets 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum chemistryA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
eGFR 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
Urine Pregnancy 
TestC 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
ECG 
XE 
X 
XE 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood Draw (for 
PK sub-study) 
XD 
 
XD 
XD 
 
 
 
 
 
 
 
 
 
 
 
Assessment of 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Imaging (CT/MRI) 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
XB 
 
Tumor 
Assessments 
(using RECIST 
criteria) 
Tumor assessments and radiologic imaging are repeated every 12 weeks during Treatment Period 
2. In subjects with an objective response, an additional tumor assessment is performed 4 weeks 
later to confirm the presence of an objective response. Documentation (CT or MRI) must be 
provided for subjects removed from study for progressive disease. 
XB 
 
Patient Diary 
Issue/CollectionJ 
I/C 
I/C 
I/C 
I/C 
I/C 
I/C 
I/C 
I/C 
I/C 
I/C 
I/C 
I/C 
I/CH 
C 
 
Subject 
Compliance 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Phone or other 
contact to 
determine 
survival 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XI 
Footnotes
A -   Phosphate, sodium, potassium, chloride, calcium, bicarbonate, creatinine, creatine kinase, glucose, blood urea nitrogen (BUN), total proteins, albumin, total 
bilirubin, alkaline phosphatase, LDH, SGOT/AST, SGPT/ALT. 
B -  Only performed on subjects discontinued for reasons other than disease progression (if not obtained within 4 weeks of withdrawal) 
C -  For women of childbearing potential. 
D -  For the subjects who consented to participate in the PK sub-study, blood samples are taken before administration of Sodium Cridanimod and megestrol acetate as 
well as 15 min, 30 min, 45 min, 60 min, 90 min, 2, 3, 4 and 6 hours (all times +/- 2 minutes) after administration at Visit 1. Blood samples are also taken on Days 3, 7, 
10, 56 (Visit 3) and 84 (Visit 4), before Sodium Cridanimod and megestrol acetate administration. 
E -  ECG will be performed 5 times at Visits 1 and 3: before Sodium Cridanimod administration, 15, 60, 120 and 360 (±5) minutes after administration. At all other visits, 
ECG is only performed before administration.  Exception:  ECG performed at Safety Follow-up Visit. 

 
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F -  Subjects with disease control (non-PD) after one year of treatment in Period 2 (Visit 13) will continue treatment and will switch to study visits every 12 weeks, until 
discontinuation of treatment. 
G -  Safety Follow-up Visit occurs four weeks following the discontinuation of treatment. 
H -  At the visit where treatment is discontinued, study drug will not be dispensed and a new patient diary will not be issued. The remaining drug will be returned and the 
final patient diary will be collected. 
I – After subjects discontinue treatment and undergo the Safety Follow-up Visit, they will be followed for overall survival for an additional 12 months (from the date of 
treatment discontinuation) by phone call or other personal contact. 
J -   D = Dispense, R = Return, I = Issue, C = Collect

 
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1. 
INTRODUCTION 
1.1. Background 
1.1.1. 
Endometrial Cancer 
Endometrial cancer is ranked as the sixth most prevalent cancer among women and is the 
fourteenth most prevalent cancer overall.. There were 320,000 new cases of endometrial cancer 
diagnosed in 2012 and there will be an estimated 500,000 cases of endometrial cancer in the 
world by 2035.  In the United States, the 5 year relative survival rate for all endometrial cancer 
cases is 69% (wcrf.org).  Endometrial cancer is now the most common gynecological 
malignancy in Europe and North America.  The median age of occurrence is 63 years; more than 
90% of women diagnosed are older than 50.1   
1.1.2. 
Progestins for the Treatment of Endometrial Cancer 
Megestrol acetate is a synthetic derivative of the naturally occurring steroid hormone 
progesterone and has been studied extensively for the treatment of endometrial cancer2–4. The 
results from several clinical trials examining the efficacy of megestrol acetate at treating subjects 
with recurrent or persistent endometrial cancer are summarized in Table 44,5. 
Table 4. Efficacy of megestrol acetate in patients with recurrent or persistent endometrial 
cancer. 
Treatment 
Overall 
response rate 
Median progression free 
survival, months 
Median overall 
survival, months 
Reference 
MA 800 
mg/day 
24% 
2.5 
7.6 
4 
MA 
NA 
NA 
12 
5 
MA + 
Tamoxifen 
NA 
NA 
8.6 
5 
It was found that subjects had increased progression-free and overall survival following 
treatment with megestrol acetate compared to placebo, leading to its FDA approval. It was also 
found that subjects whose tumors expressed the progesterone receptor (PrR) had a significantly 
higher response rate than those subjects who did not express PrR. For this reason, progestins 
are typically only used in patients with documented PrR-positive endometrial cancer. However, 
PrR-expression’s predictive power is still limited, as the response rate even in these subjects is 
only approximately 25%. 
Table 5. Response rate to progestin therapy by PrR status 
Characteristic 
Overall response rate 
Median overall survival, months 
Histologic grade 1 
37% 
18.8 
Histologic grade 2 
23% 
7.5 
Histologic grade 3 
9% 
6.9 
PrR level, ≥ 50 fmol/mg cytosol protein 
37% 
12.1 
PrR level, < 50 fmol/mg cytosol protein 
8% 
6.8 

 
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1.2. Sodium Cridanimod 
For the most complete and up-to-date information regarding Sodium Cridanimod, refer to the current 
version of the Investigator’s Brochure.   
Sodium Cridanimod (oxodihydroacridinylacetate sodium) is a synthetic interferon inducer that was 
developed in the 1970s-80s by Hoffman-La Roche Inc6,7. In preclinical models, Sodium Cridanimod 
was shown to protect against lethal Semliki Forest, Coxsackie Bi, Columbia SK, Western equine 
encephalitis, herpes simplex, and pseudorabies virus infections8. A number of clinical studies 
performed in the former Soviet Union and Russian Federation demonstrated its safety and efficacy in 
humans, and lead to its current approval in the Russian Federation and many Eastern European 
countries for the treatment of many viral infections. To date, no clinical trials with Sodium Cridanimod 
have been performed in the United States and Canada. 
1.2.1. 
Nonclinical Data Relevant to Endometrial Cancer 
An early animal study revealed that Sodium Cridanimod administration to rats for a 2-week 
period significantly increased the endometrial expression of PrR and that the magnitude of the 
effect was similar, and additive, to that of tamoxifen8. A subsequent animal study examined the 
efficacy of Sodium Cridanimod in combination with medroxyprogesterone acetate (a synthetic 
progestin, similar to megestrol acetate) on treating xenograft Hec50co endometrial tumors, a 
tumor line known to be PrR-negative. This study demonstrated that the addition of Sodium 
Cridanimod could significantly increase the anti-tumor efficacy of medroxyprogesterone acetate 
when targeting an otherwise PrR-negative endometrial cancer. Taken together, these findings 
suggest a mode of action for Sodium Cridanimod, namely that Sodium Cridanimod can increase 
the expression of PrR on endometrial tumors subsequently making them more amenable to 
treatment with traditional progestin therapy. 
1.2.2. 
Clinical Data Relevant to Endometrial Cancer 
An early clinical study conducted in the Russian Federation enrolled 50 subjects with untreated 
stage I-II endometrial cancer. Subjects were treated with either Sodium Cridanimod (250 mg 
every 3 days), medroxyprogesterone acetate (500 mg daily), or a combination of the two for 
three weeks prior to hysterectomy. The results of this study revealed that Sodium Cridanimod 
significantly increased the PrR levels in tumors that were negative for PrR prior to treatment. 
A second clinical study, designed similarly to this study, enrolled 28 subjects and treated them 
initially with medroxyprogesterone acetate (250 mg daily). After these subjects progressed on 
progestin monotherapy, they then received a combination of Sodium Cridanimod (250 mg, twice 
weekly) and medroxyprogesterone acetate. In this study, the subjects who failed 
medroxyprogesterone acetate monotherapy had a 100% response rate to the combination 
therapy, whereas the subjects who initially had a response to medroxyprogesterone acetate and 
then later progressed only had a 33% response rate to the combination therapy. 
Taken together, these studies demonstrate that Sodium Cridanimod can increase the levels of 
PrR expression in endometrial tumors and can make them more amenable to treatment with 
progestin therapy. These data also demonstrate that the effect of combining Sodium Cridanimod 

 
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with progestin therapy may be most pronounced in subjects for whom progestin monotherapy 
demonstrates no efficacy. 
1.3. Summary of Key Safety Information for Study Drug 
Acute toxicity of Sodium Cridanimod has been studied in mice, rats, hamsters and rabbits, with 
intramuscular administration not shown to cause deaths in any of these species. Repeated dose 
toxicity studies have been performed in rats, rabbits and dogs. These studies have not identified any 
target organ toxicity at doses as high as 31.3 mg/kg i.m. Sodium Cridanimod is known to be eliminated 
mostly by the kidney with a half-life of approximately 0.6 hours. 
More than 750 subjects have been exposed to Sodium Cridanimod in clinical studies. The regimen of 
administration of Sodium Cridanimod was similar across clinical studies: study drug was administered 
at the dose of either 250 or 500 mg either two or three times a week intramuscularly, in some cases for 
as long as 2 years.  All of these trials have demonstrated that Sodium Cridanimod is well tolerated, 
with mild to moderate adverse events (AEs) and no subjects ever permanently discontinuing study 
drug due to an AE related to administration of Sodium Cridanimod. The most frequently reported AE 
across the studies was moderate intensity pain at the site of injection. There have been no deaths 
associated with the administration of Sodium Cridanimod. Table 6 below summarizes the related, AEs 
observed in all subjects who were treated with Sodium Cridanimod in all studies to date. 
Table 6.  Adverse Events with causal relationship to Sodium Cridanimod  
Adverse Event 
Investigator 
Causality 
Assessment 
AE Frequency 
per Study 
Total Subjects 
with reported 
AE to date* 
Frequency of 
AE based on 
total Subjects 
treated* 
Burning pain at the injection site 
Related 
729 of 751 (97%) 
730 
96.18 % 
Relative eosinophilia 
Probably related 
6 of 50 (12%) 
6 
0.79 % 
Burning Lips 
Probably related 
1 of 8 (13%) 
1 
0.13 % 
Fatigue and tired all the time 
Probably related 
1 of 8 (13%) 
1 
0.13 % 
Hyperemia of the face  
Probably related 
1 of 8 (13%) 
1 
0.13 % 
Pharyngalgia 
Probably related 
1 of 8 (13%) 
1 
0.13 % 
Sleepiness 
Probably related 
1 of 8 (13%) 
1 
0.13 % 
Headache 
Possibly related 
4 of 12 (33%), 
1 of 8 (13%) 
5 
0.66 % 
Sore throat 
Possibly related 
4 of 12 (33%), 
1of 8 (13%) 
5 
0.66 % 
Weakness 
Possibly related 
2 of 6 (33%), 
1 of 8 (13%) 
3 
0.40 % 
Dizziness 
Possibly related 
2 of 6 (33%) 
2 
0.26 % 
Sleepiness 
Possibly related 
2 of 6 (33%) 
2 
0.26 % 
*Data from 759 subjects in clinical trials through 1Sep2017
All AEs determined by the Investigator to have an unrelated causality to Sodium Cridanimod occurred 
in a frequency less than 1% in all treated subjects.  

 
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Additionally, safety and tolerability of Sodium Cridanimod was assessed in a post-registration study in 
healthy subjects, where subjects were treated twice weekly with either Sodium Cridanimod (500 mg), 
Sodium Cridanimod (500 mg) + 2% lidocaine hydrochloride, or placebo. The main purpose of this 
study was to assess the safety and tolerability of Sodium Cridanimod at a dose of 500 mg and whether 
the injection site pain could be lessened by the addition of lidocaine hydrochloride solution to the 
injection. Overall, repeated intramuscular injections of 500 mg Sodium Cridanimod with or without  
lidocaine were well tolerated by these healthy volunteers, with no significant changes in blood 
pressure, heart rate, ECG, or physical or clinical laboratory parameters. Table 7 below summarizes the 
nature and frequency of all AEs experienced by subjects during the study. Four AEs of sore throat were 
rated as “probably related” to the use of study medication. 
Table 7. Summary of AEs related to Sodium Cridanimod in post-registration safety and 
tolerability study in healthy subjects 
Study treatment 
Sodium Cridanimod 
500 mg i.m. twice a 
week 
Sodium Cridanimod  
500 mg i.m. 
+ 2% Lidocaine 
hydrochloride  
1 mL twice a week 
0.9%Sodium chloride  
 4 mL i.m. twice a 
week 
(placebo) 
Number of subjects 
12 
12 
12 
Pain at the injection site 
10 
4 
1 
Sore throat 
1 
3 
0 
Sodium Cridanimod is approved for marketing in the Russian Federation, Republic of Belarus, Ukraine, 
Republic of Uzbekistan, Republic of Azerbaijan, Republic of Kazakhstan, Kyrgyz, Republic of Georgia 
and Republic of Armenia for the treatment of several viral infections including in immunodeficient 
patients. The data from marketing experience indicates treatment with Sodium Cridanimod is well 
tolerated, as more than 1.4 million doses have been sold to date and no SAEs have been reported as 
documented in periodic safety update reports. 
1.3.1 
Adverse Reactions Reported with Megestrol Acetate 
Adverse events associated with the use of megestrol acetate as reported in the current, 
marketed package insert9 include:  Weight gain as a frequent side effect. Thromboembolic 
Phenomena including thrombophlebitis and pulmonary embolism (in some cases fatal). 
Glucocorticoid effects, heart failure, nausea and vomiting, edema, breakthrough menstrual 
bleeding, dyspnea, tumor flare (with or without hypercalcemia), hyperglycemia, glucose 
intolerance, alopecia, hypertension, carpal tunnel syndrome, mood changes, hot flashes, 
malaise, asthenia, lethargy, sweating and rash.  The investigator should refer to the current 
prescribing information for complete information including contraindications, warnings and 
precaution information. A copy of the current package insert is included in the Pharmacy Manual 
for this study. 
1.3.2 
Adverse Reactions Reported with Lidocaine Hydrochloride 
Lidocaine HCL is mixed with Sodium Cridanimod for each injection. Adverse events associated 
with the use of lidocaine HCL as reported in a current, marketed package insert10 include those 
most commonly reported:  

 
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Central Nervous System: CNS manifestations are excitatory and/or depressant and may be 
characterized by lightheadedness, nervousness, apprehension, euphoria, confusion, 
dizziness, drowsiness, tinnitus, blurred or double vision, vomiting, sensations of heat, cold or 
numbness, twitching, tremors, convulsions, unconsciousness, respiratory depression and 
arrest. The excitatory manifestations may be very brief or may not occur at all, in which case 
the first manifestation of toxicity may be drowsiness merging into unconsciousness and 
respiratory arrest.  Drowsiness following the administration of lidocaine HCl is usually an 
early sign of a high blood level of the drug and may occur as a consequence of rapid 
absorption.  
Cardiovascular System: Cardiovascular manifestations are usually depressant and are 
characterized by bradycardia, hypotension, and cardiovascular collapse, which may lead to 
cardiac arrest.  
Allergic:  Allergic reactions are characterized by cutaneous lesions, urticaria, edema or 
anaphylactoid reactions. Allergic reactions may occur as a result of sensitivity either to local 
anesthetic agents or to the methylparaben used as a preservative in the multiple dose vials. 
Allergic reactions as result of sensitivity to lidocaine HCl are extremely rare and, if they 
occur, should be managed by conventional means. The detection of sensitivity by skin 
testing is of doubtful value.   
Serious adverse experiences are generally systemic in nature.  The investigator should refer to 
the current prescribing information for complete information including contraindications, warnings 
and precaution information. A copy of the current package insert is included in the Pharmacy 
Manual for this study. 
1.4 Rationale for Study 
Patients with recurrent or persistent endometrial cancer have limited treatment options. Although 
treatment with progestins provides some benefit and is routinely used to treat patients with PrR-
positive recurrent or persistent tumors, only 25% of patients develop a response to these therapies, 
leaving a majority of the patients with few other options for treatment. Additionally, patients whose 
tumors do not express PrR are rarely treated with hormonal therapy as the response rate for these 
treatments in PrR-negative tumors is very low.  As such, hormone resistant recurrent or persistent 
endometrial cancer represents a patient population for which new treatment options are greatly 
needed. Sodium Cridanimod has been shown to increase endometrial cancer expression of PrR and 
increase the efficacy of progestin therapy in at least a subset of these patients, which we believe 
provides a strong rationale for the combination of these agents for the treatment of recurrent or 
persistent endometrial cancer that has failed hormonal therapy. Additionally, combining progestin 
therapy with other agents known to increase tumor PrR expression (such as tamoxifen) has shown 
some success in other studies, supporting the rationale for this study11,12. 
1.5. Rationale for Study Population, Exclusion Criteria 
This study will enroll patients with endometrioid histology of the tumor as endometrioid tumors have 
been shown to be the most sensitive to treatment with hormonal therapy. Additionally, the majority of 
the tumors previously treated with Sodium Cridanimod and progestins were of the endometrioid 

 
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histology. The efficacy of the study treatment in patients with other tumor histologies, or mixed 
histologies, is difficult to predict. For this reason, inclusion of patients with tumors of other histologies 
or mixed histology is prohibited with the exception of serous carcinoma13.  Patients with serous 
carcinoma are eligible to enter this protocol as this histology was included in a prior trial of Sodium 
Cridanimod and progestin therapy in recurrent or persistent endometrial cancer with PrR negative 
tumors.   
Endometrial cancer patients whose tumors do not express progesterone receptors are not considered 
candidates for progestin-based therapy. Patients therefore who have been identified as PrR negative 
from an archived tumor tissue sample will not be treated with progestin monotherapy and will enroll 
directly into the combination therapy portion of the trial. 
As the main elimination route of Sodium Cridanimod is the kidney, patients with significant kidney 
disease and a diminished glomerular filtration rate (GFR < 50 mL/min) will not be enrolled in the study. 
eGFR will be monitored during the study for safety reasons. In the event of an observed renal toxicity, 
the decision to withdraw the treatment should be made by the Investigator. 
1.6. Rationale for Selection of Dose of Study Drug 
The dosage of Sodium Cridanimod (500 mg, twice weekly) was chosen because it was shown to be 
well tolerated in safety evaluations and evidence from preclinical models demonstrated this dosage 
(per kg) to have the best activity. Intramuscular administration was selected based on preclinical 
studies demonstrating other routes were not feasible or offered no advantage over i.m. administration. 
Oral bioavailability of Sodium Cridanimod was shown to be very low, and repeated intravenous 
administration of Sodium Cridanimod was shown to potentially induce phlebitis. 
As the intramuscular injection of Sodium Cridanimod has been shown to cause moderate pain at the 
site of injection, this study will dilute the Sodium Cridanimod (4 mL, 500 mg) with 1 mL of 2% lidocaine 
hydrochloride, a local anesthetic solution. The resulting 5 mL dosage was shown to be well tolerated in 
the post-registration study noted above and was shown to decrease the frequency of injection site 
pain. 
The dosage of megestrol acetate (160 mg / day) is in accordance with the most up-to-date prescribing 
information provided by the commercial vendor. 
1.7. Rationale for Treatment Duration 
Previous trials examining the efficacy of progestin monotherapy at treating advanced endometrial 
cancer demonstrated an objective response rate (ORR) of approximately 25% with disease 
stabilization (no progression) for an average duration of 9 months. Progestin therapies for endometrial 
cancer are administered for long periods of time in order to constantly expose the tumor cells to the 
progestins, and this prolonged exposure has been shown to be safe and well-tolerated. 
However, prolonged exposure of tumor cells to progestins has been demonstrated to downregulate the 
expression of PrR in tumor tissue as the tumor cells become desensitized to the repressive signaling 
induced by the progestins. As such, we believe prolonged treatment with Sodium Cridanimod in 
conjunction with prolonged progestin treatment is a rational treatment approach. Sodium Cridanimod 
has been demonstrated to be safe when given 2-3 times per week for as long as 2 years of 
administration. A recent Gynecologic Oncology Group demonstrated the safety of prolonged treatment 

 
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of advanced endometrial cancer patients with megestrol acetate in combination with tamoxifen, a 
similar inducer of PrR expression. Therefore, we believe that the continuous treatment of hormone 
resistant recurrent or persistent endometrial cancer with megestrol acetate in combination with Sodium 
Cridanimod until documented disease progression will be well tolerated and provide the greatest 
chance at observing objective anti-tumor responses, disease stabilization, and increased overall 
survival. 
2. 
STUDY OBJECTIVE(S), DESIGN AND ENDPOINTS 
2.1. Study Objectives 
2.1.1. 
Primary Objective 
To assess the antitumor activity of Sodium Cridanimod in conjunction with progestin therapy as 
measured by Overall Disease Control Rate (ODCR) in women with recurrent or persistent 
endometrial carcinoma not amenable to surgical treatment or radiotherapy who have either failed 
progestin monotherapy or who have been identified as PrR negative. 
2.1.2. 
Secondary Objective 
Efficacy: To assess ORR including PR and CR, PFS, Duration of Stable Disease and OS for 
subjects receiving Sodium Cridanimod and possibly in conjunction with progestin therapy. 
Safety: To evaluate the safety and tolerability of Sodium Cridanimod possibly in conjunction with 
progestin therapy as measured by adverse events, laboratory safety parameters, and cardiac 
safety assessments (including QT prolongation potential). 
2.1.3. 
Translational Research Objective 
To assess pharmacokinetics of Sodium Cridanimod and megestrol acetate after a single dose 
and after multiple dose administrations and possible drug-drug interactions between Sodium 
Cridanimod and megestrol acetate. 
 
2.2. Study Design 
This is an open-label, multi-center, single-arm, two-period Phase 2 study. The study will investigate the 
efficacy of Sodium Cridanimod in conjunction with progestin therapy in a population of patients with 
endometrial cancer who have either failed progestin monotherapy or who have been identified as PrR 
negative.  
All patients must have endometrial cancer PrR status determined from an archival sample at Screening. 
The tumor is considered to be PrR negative if the number of PrR positive cells is less than 1% determined 
by use of IHC.  Conversely, the tumor is considered to be PrR positive if the number of PrR positive cells 
is 1% or greater as determined by IHC.  
 
There are two treatment periods and a follow-up period within the study.  
2.2.1  
Treatment Period 1 (Progestin Monotherapy):   
During Treatment Period 1, all eligible subjects determined to be PrR positive will receive 
progestin monotherapy (megestrol acetate 160 mg p.o. / day) for up to 24 weeks. Subjects will 

 
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have a CT or MRI scan after 12 and 24 weeks of progestin monotherapy, with response to 
treatment being assessed according to RECIST 1.1 criteria.  
 
At Visit -1 (After 12 weeks of treatment):  
• 
Subjects determined to have disease progression will be eligible to enter Treatment 
Period 2.   
• 
Subjects who maintain disease control (SD, PR or CR) may continue progestin 
monotherapy for an additional 12 weeks. These subjects will be re-assessed after 24 
weeks of treatment (TP1-EXT Visit).  
o 
Subjects determined to have disease progression will be eligible to enter 
Treatment Period 2.  
o 
Subjects who maintain disease control will be ineligible to enter Treatment 
Period 2. These subjects will return 2 weeks following the TP1-EXT Visit for the 
End of Study Visit. 
 
A subject may be discontinued from Treatment Period 1 at any time if the subject experiences a 
change in symptoms and/or if disease progression is suspected by the Investigator.  
• 
Subjects who discontinue Treatment Period 1 prematurely (receiving < 4 weeks of 
progestin monotherapy) for any reason will be excluded from the remainder of the study. 
• 
Subjects who have had ≥ 4 weeks of progestin monotherapy and have documented 
disease progression may enter Treatment Period 2 at Visit 1, Day 0. 
 
Subjects who terminate study participation at the end of Treatment Period 1 due to disease 
control will be treated in accordance with local standards and clinical practice (which can include 
continuation of progestin therapy).   
 
Subjects determined to be PrR negative at Screening will not enroll into Treatment Period 1. 
These subjects will enroll directly into Treatment Period 2. 
2.2.2  
Treatment Period 2 (Combination Therapy):   
All subjects determined to be PrR negative at Screening and those who received at least 4 
weeks of progestin monotherapy and who experienced disease progression during Treatment 
Period 1 will enter Treatment Period 2 of the study (Visit 1, Day 0). 
  
During Treatment Period 2, subjects will receive Sodium Cridanimod (500 mg, 2 times / week, 
intramuscularly) in combination with continued progestin treatment (megestrol acetate 160 mg 
p.o. / day).  
• 
For those subjects who participated in Treatment Period 1, there should be no 
interruption of progestin therapy between Treatment Period 1 and Treatment Period 2.  
• 
Subjects will receive treatment until disease progression as defined according to 
RECIST 1.1 Criteria, with response assessments performed at 12-week intervals.  

 
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• 
Confirmation of objective responses in Treatment Period 2 will be performed at least 4 
weeks after the criteria for response are first met. 
2.2.3 
Follow-up Period:   
Once subjects progress in Treatment Period 2, treatment will be stopped and the subjects will 
return for the Safety Follow-up Visit four (4) weeks following the last treatment, and then 
continue to be followed for a 12-month period for overall survival. 
2.3. Endpoints 
Subjects will be discontinued from the study (during Treatment Period 2) at the time of radiographic 
(CT/MRI) disease progression, relative to baseline measurements from the scan that determined the 
subject was eligible to participate in Treatment Period 2 of the study (i.e. scan typically taken at Week -
1 or at TP1-EXT). Subjects will also be discontinued from the study when, at the discretion of the 
subject or treating physician, continuing treatment is not in their best interest and/or that other standard 
therapies for endometrial cancer are warranted.  
2.3.1. 
Primary Endpoint 
The primary endpoint of the trial is overall disease control (SD, CR or PR) as determined by 
radiographic measurements. All subjects in Treatment Period 1 will undergo radiographic 
imaging (CT or MRI scan of chest, abdomen and pelvis) prior to treatment, after 12 weeks of 
progestin monotherapy (at Visit -1), and if disease control is maintained, again after an additional 
12 weeks of progestin monotherapy (at Visit TP1-EXT). During Treatment Period 2, subjects will 
undergo a CT or MRI scan at 12-week intervals. Subjects may also be assessed at any point 
when the Investigator determines radiographic imaging is indicated. Radiographic disease 
progression and responses will be defined using RECIST 1.1 criteria as detailed in Section 5.5, 
and the ODCR will be determined as described in Section 7.4. 
2.3.2. 
Secondary Endpoints 
The secondary endpoints of the trial include safety and other efficacy parameters. As before, 
radiographic imaging will be used to assess the ORR, PFS, duration of stable disease, and OS. 
A more detailed description of how these will be calculated is included in Section 7.4. Safety will 
be assessed as described in Sections 5.7 and 5.9. 
 
3. STUDY POPULATION 
3.1. Selection of Study Population 
This study will enroll subjects with recurrent or persistent endometrial cancer. 
3.2. Informed Consent 
Before any study-related screening procedure is performed, each potential subject will be informed of 
the study's objectives and requirements. The Investigator or his/her designee will explain the study fully 
to the subject using the Informed Consent Form (or Patient Information Sheet, as applicable in some 
countries). If the subject is willing to participate in the study, written informed consent will be requested 
after sufficient time to consider participation and the opportunity to ask further questions has been 

 
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given. The Informed Consent Form will be signed and personally dated by both the subject and the 
person obtaining the consent. The person obtaining consent must be the Investigator or his/her 
designee who is also medically qualified. The subject will be provided a copy of the signed and dated 
Informed Consent Form. The original signed and dated Informed Consent Form will be retained with 
the source documents.  
3.3. Screening 
Following the receipt of informed consent, potential subjects will be assigned a subject identification 
number and undergo screening procedures to determine eligibility for the study. Screening procedures 
will be conducted according to the Visit and Assessment Schedule described in Section 5.4. 
3.4. Inclusion Criteria 
1. Female patients 18 years of age or older; 
2. Histologically confirmed serous carcinoma or endometrioid type of endometrial carcinoma 
(histological documentation of recurrence is not required); 
3. Recurrent or persistent progressive disease which is refractory to curative therapy or 
established treatments and cannot be treated with surgery or radiotherapy; 
4. Measurable disease, as defined by RECIST 1.1 criteria; 
5. At least one “target lesion” to be used to assess response, as defined by RECIST 1.1 
criteria. Tumors within a previously irradiated field will be designated as “non-target” lesions 
unless previous progression is documented; 
6. Availability of archived tumor tissue sample that can be used for assessment of PrR status 
by the central laboratory; 
7. GOG performance status 0-2 (refer to Table 9 under Section 5.5.3); 
8. eGFR ≥ 50 mL/min; 
9. Total bilirubin ≤ 2.5 times upper limit of normal (ULN); 
10. AST ≤ 2.5 ULN (≤ 5 times ULN for patients with liver metastases); 
11. Alkaline phosphatase ≤ 2.5 ULN (≤ 5 times ULN for patients with liver metastases); 
12. Albumin ≥ 3.0 mg/dL; 
13. Ability to take oral medication 
14. Patients able to understand the nature of the study and who are willing to give written 
informed consent; 
15. And or Treatment Period 2 only, Patients participating in Treatment Period 1 must have had 
disease progression after receiving at least 4 weeks of progestin therapy or 2) Patients must 
be determined as PrR negative status at Screening.  
Waivers to the inclusion criteria will NOT be allowed. 

 
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3.5. Exclusion Criteria 
1. Mixed histology of the tumor or evidence of tumor histology other than serous carcinoma or 
endometrioid type of endometrial carcinoma; 
2. Concurrent systemic corticosteroid therapy; 
3. Concurrent oral contraceptive use / Women of childbearing potential not using highly 
effective means of contraception; 
4. Pregnancy confirmed by pregnancy test / Lactating women (for women of childbearing 
potential); 
5. Prior therapy with hormonal progestin agents; 
6. Patients who are candidates for treatment with standard chemotherapy agents (there is no 
limit to the number of lines of prior chemotherapy);  
7. History of blood clot; 
8. History of known bleeding disorder (i.e. disseminated intravascular coagulation or clotting 
factor deficiency); 
9. Major surgery within 4 weeks prior to the start of the study; 
10. Patients with clinically significant illnesses which, according to the Investigator, could 
compromise participation in the study; 
11. History of other clinically active malignancies within 5 years, except for carcinoma in situ of 
the cervix, basal cell carcinoma, or squamous carcinoma of the skin. 
12. Known hypersensitivity or idiosyncratic reaction to any of the study drugs (Sodium 
Cridanimod, megestrol acetate, lidocaine) and excipients; 
13. Patients with known brain metastases; 
14. Patients currently receiving any other investigational agents; 
15. Patients currently receiving any other anticancer therapies; 
16. Participation in any other clinical study within the last 4 weeks prior to the start of the study; 
Waivers to the exclusion criteria will NOT be allowed. 
 
3.6. Discontinuation Criteria for Individual Subjects 
Treatment may continue until one of the following criteria applies: 
• 
Disease progression (during Treatment Period 2 only), 
• 
A Grade 3 or higher AE (according to NCI-CTCAE Version 4 criteria) is observed and is 
determined to be related to either the Sodium Cridanimod or progestin therapy. 
• 
Concurrent illness that prevents further administration of treatment, 
• 
Unacceptable AE(s), 

 
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• 
Patient decides to withdraw from the study, or 
• 
General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the judgment of the Investigator. 
3.7. Patient Requirements 
The following patient requirements apply from screening through completion or withdrawal of the study: 
• 
Patients must have the availability to attend visits according to the protocol; 
• 
Patients must not participate in any other clinical study; 
• 
Patients of childbearing potential must use highly effective barrier contraception; 
• 
Patients must keep a diary of megestrol acetate doses as described in Section 5.7.7. 
3.8. Subject Identification 
Subjects in this study will be identified only by the subject number (CCC-SS-XX), which consists of a 3-
digit country code (CCC), a 2-digit site number (SS) followed by 2-digit consecutive enrollment number 
(XX) of subjects enrolled at the specific clinical site.  
 
4. STUDY DRUG 
4.1. Description of Study Drugs 
For the most recent, detailed pharmaceutical information on Sodium Cridanimod and megestrol 
acetate, refer to the Sodium Cridanimod Investigator’s Brochure and the Prescribing Information for 
megestrol acetate. 
4.1.1  
Sodium Cridanimod is a synthetic interferon inducer that has been extensively studied 
and is approved for many indications (mainly viral infections) in the Russian Federation and 
other Eastern European countries. Sodium Cridanimod (125 mg/mL) will be supplied to the 
investigational sites as a ready-to-use solution in ampules. One ampoule contains 2 mL, or 250 
mg, of Sodium Cridanimod. 
4.1.2  
Megestrol acetate  is a synthetic derivative of the naturally occurring hormone 
progesterone and is FDA approved for the treatment of advanced endometrial cancer. Megestrol 
acetate will be supplied in tablet form in doses of either 40 or 160 mg (depending on approved 
dosage forms in the applicable country).   
4.1.3  
Lidocaine Hydrochloride is a local anesthetic that is commonly used in clinical 
settings. It will be provided by the Investigator’s pharmacy as a 2% (w/v) aqueous solution. As 
described in detail below, lidocaine will be mixed with Sodium Cridanimod to increase tolerability 
of the intramuscular injection. 
4.2. Preparation of Sodium Cridanimod 
To administer Sodium Cridanimod, the contents of 2 ampules (4 mL of solution equal to 500 mg of 
Sodium Cridanimod) and 1 mL of 2% lidocaine hydrochloride solution (for a total administration volume 
of 5 mL) should be withdrawn with a syringe. After the contents of the syringe are mixed, and all air 

 
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and air bubbles are removed from the syringe, the resulting solution is administered intramuscularly. It 
is preferable to rotate injection sites with each dose. 
4.3. Study Drug Handling 
Sodium Cridanimod may be requested by the Principal Investigator (or authorized designee) at each 
participating institution and will be shipped directly to the institution where the subject is to be treated. 
The Investigator/pharmacist is responsible for safe and proper handling and storage of the study drugs 
at the investigational site.  The study drugs must be stored in a secure area.  Access to and 
administration of study drugs will be limited to the Investigator and authorized site personnel. The 
Investigator must ensure that study drugs are administered or dispensed only to subjects enrolled in 
this study and in accordance with the protocol. The study drugs must be stored at room temperature. 
Temperature logs should be kept updated by the Investigator, pharmacist or designated site personnel 
to document adequate storage during the course of the study. 
It is the responsibility of the Investigator or, if applicable, pharmacist or designated site personnel to 
ensure that records of receipt, use by each subject, return, loss, or other disposition of study drugs are 
maintained at each study site. These records will include dates, quantities, batch numbers, and the 
unique subject numbers assigned to subjects. The Investigator must maintain records documenting 
that the subjects were provided with the doses specified in the protocol. Furthermore, they should 
reconcile all study drugs received from the Sponsor. It is the responsibility of the Investigator to give 
reasons for any discrepancies in study drug accountability and inventory. Study related forms and logs 
will be provided by the Sponsor to enhance drug accountability and inventory.  All remaining study 
drugs shall be collected and disposed of according to the Sponsor’s directions at the end of the study. 
 
5. 
TREATMENTS AND EVALUATION 
5.1. Dosing and Administration of Study Drugs and Other Medications 
5.1.1. 
Dose/Dose Regimen and Administration  
5.1.1.1   Megestrol acetate is supplied as either 40 mg (US) or 160 mg (Europe) 
tablets. For 40 mg tablets, two tablets are administered orally, twice daily, for a total daily 
dose of 160 mg. For 160 mg tablets, one tablet is administered orally, once daily, for a 
total daily dose of 160 mg.   
At Study Visits when both megestrol acetate and Sodium Cridanimod are to be 
administered, the dose of megestrol acetate should be administered prior to Sodium 
Cridanimod. Whenever possible, the a.m. or p.m. dose of megestrol acetate should be 
taken in the clinic during the Study Visit. 
5.1.1.2   Sodium Cridanimod solution is administered twice weekly according to either 
Schedule 1 (Mondays and Thursdays) or Schedule 2 (Tuesdays and Fridays) until 
documented disease progression, according to Table 8. For scheduled Sodium 
Cridanimod administrations that do not coincide with Study Visits, the Sodium 
Cridanimod can be administered either at the study site or at a subject’s home by a 
medical service provider.  

 
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Table 8: Schedule of Sodium Cridanimod Administration 
 
Weekly until Disease Progression 
 
Monday  
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
Sunday 
Schedule 1 
500 mg  
i.m. 
 
 
500 mg 
i.m. 
 
 
 
Schedule 2 
 
500 mg 
i.m. 
 
 
500 mg 
i.m. 
 
 
5.1.2. 
Dose Modifications 
There will be no allowed modifications to the dosage, including dose reduction, of either 
megestrol acetate or Sodium Cridanimod during the trial.  
If injection of Sodium Cridanimod was not administered on the scheduled dosing date, this can 
be done during the next two days but not later than 1 day before the next scheduled dose. The 
subsequent injection of Sodium Cridanimod should be given according to the study drug 
administration schedule. 
If a subject misses a dose of megestrol acetate, the next dose should be taken at the regularly 
scheduled time. 
Sodium Cridanimod and megestrol acetate combination therapy should be discontinued if an AE 
of Grade 3 or higher (according to NCI-CTCAE Version 4 criteria) is observed and determined to 
be potentially related to either medication.  When combination treatment is discontinued, both 
Sodium Cridanimod and megestrol acetate are to be discontinued. Monotherapy in Treatment 
Period 2 is not permitted.  The treatment will not be re-started and the subject will be withdrawn 
from Treatment Period 2. The subject will then enter the Follow-up Period as described in 
Section 5.1.4.   
5.1.3. 
Duration of Therapy 
5.1.3.1 
Treatment Period 1:  Subjects will participate in Treatment Period 1 for up 
to 24 weeks, during which time they are receiving only megestrol acetate.  If a subject 
terminates therapy early in Treatment Period 1 for reasons outlined in Section 3.6, they 
will not be eligible to enter Treatment Period 2.  They will have an End of Study Visit, 
and then be treated in accordance with local standards of clinical practice.   
5.1.3.2   
Treatment Period 2:  Subjects who qualify to participate in Treatment 
Period 2 will receive both megestrol acetate and Sodium Cridanimod until documented 
disease progression.  If a subject terminates therapy early in Treatment Period 2 for 
reasons outlined in Section 3.6, they will enter the Follow-up Period and then be treated 
in accordance with local standards of clinical practice.   
5.1.4. 
Duration of Follow-up 
There is no follow-up period for subjects exiting the study during or at the end of Treatment 
Period 1; they will continue to be treated in accordance with local standards of clinical practice. 

 
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Subjects who have participated in Treatment Period 2 and exit the study for any reason will enter 
the Follow-up Period.  These subjects will return to the site 4 weeks following the discontinuation 
of treatment for the Safety Follow-up Visit.  Subjects will then be followed for a 12-month period 
to determine overall survival.  No additional visits are required after the Safety Follow-up Visit.  
Study staff will confirm survival status via telephone, personal contact or through clinic records, 
once, at the end of the 12 month period. This outcome is to be recorded in the eCRF. 
5.1.5. 
Subject Compliance 
Treatment compliance will be monitored by the review of study drug accountability, inventory 
records by study personnel, and patient diaries. Subject compliance (for each study drug 
individually) lower than 80% or higher than 120% will be considered a major protocol violation. In 
the case of poor compliance, the reason for the discrepancy will be documented in the eCRF 
and the Investigator, together with the Sponsor, will decide on a clinical basis as to whether the 
subject may remain in the study. 
5.2. Demographics and Baseline Characteristics 
5.2.1. 
Demographics 
Year and month of birth, weight, height, and ethnic origin will be recorded. 
5.2.2. 
Medical History 
All current medical conditions, including endometrial cancer and any significant past conditions, 
surgeries, tobacco and alcohol consumption, previous therapeutic or diagnostic procedures, and 
all concomitant medications will be recorded. 
5.3. Assessment of PrR Status at Screening 
The PrR status of the endometrial cancer is determined at screening, through the assessment of 
an archived tumor sample. The archived sample should preferably be provided within Formalin-
fixed Paraffin Embedded (FFPE) Block, but slides are acceptable. For confirmation of PrR status, 
the patient’s tumor sample is sent to the central laboratory. Levels of PrR are determined with the 
use of semi-quantitative IHC.  The tumor is considered to be PrR negative if the number of PrR 
positive cells is less than 1% determined by IHC.  Conversely, the tumor is considered to be PrR 
positive if the number of PrR positive cells is 1% or greater as determined by IHC. 
It is preferable to send the most recently obtained tumor sample whenever possible.  Patients who 
cannot have PrR status confirmed by the central lab will be excluded from study participation. 
5.4. Visit Schedule and Required Study Procedures 
5.4.1. 
Screening (Time Frame: ≤ 4 weeks from the start of Treatment Period 1, Week -18 to 
-15) 
• 
Informed consent 
• 
Eligibility criteria 
• 
Demographics 
• 
Medical history 
• 
Concomitant medication review 
• 
Physical exam 
• 
Vital signs 

 
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• 
Height 
• 
Weight 
• 
Performance status 
• 
CBC with differential, platelets 
• 
Serum chemistry 
• 
eGFR 
• 
Urinalysis 
• 
Serum pregnancy test (for women of childbearing potential) 
• 
ECG 
• 
AE evaluation 
• 
Confirmation of PrR status in central laboratory of archived tumor sample (Specimen 
should be sent to central lab during Screening Weeks -18 and -16 to ensure results 
are received prior to Study Visit -3).  
• 
CT/MRI Scan  
• 
Tumor assessment and measurements (Radiologic evaluation must be obtained 
within 10 days of Visit -3). 
 
5.4.2. 
Treatment  
Treatment Period 1 – Patients determined to have PrR Positive Status Only 
Visit -3 (Week -14, ± 3 days) *  
• 
Eligibility criteria 
• 
Concomitant medication review 
• 
Vital signs 
• 
ECG 
• 
For optional PK Sub-Study Participants:   
o 
Collection of blood samples for optional PK sub-study, at 10 timepoints: 0 
(before administration of megestrol acetate), and 1, 2, 3, 4, 6, 24, 48, 72 and 
96 hours (all times +/- 2 minutes) after administration).   
• 
AE evaluation 
• 
Administration of megestrol acetate  
• 
Dispense supply of megestrol acetate  
• 
Issue patient diaries 
 
* If Visit -3 occurs > 7 days after the Screening visit, the following assessments 
should also be performed: 
• 
Physical exam 
• 
Weight 
• 
Performance status 
• 
CBC with differential, platelets 
• 
Serum chemistry 
• 
eGFR 

 
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Visit -2 (Week -8, ± 3 days) 
• 
Concomitant medication review 
• 
Physical exam 
• 
Vital signs 
• 
Weight 
• 
Performance status 
• 
CBC with differential, platelets 
• 
Serum chemistry 
• 
eGFR 
• 
ECG 
• 
AE evaluation 
• 
Assess subject dosing compliance 
• 
Collect completed patient diary(ies) and issue new diary(ies) 
• 
Administration of megestrol acetate  
• 
Collect any empty bottle(s) of megestrol acetate and dispense new supply 
Visit -1 (Week -2, ± 3 days) 
• 
Concomitant medication review 
• 
Physical exam 
• 
Vital signs 
• 
Weight 
• 
Performance status 
• 
CBC with differential, platelets 
• 
Serum chemistry 
• 
eGFR 
• 
ECG 
• 
AE evaluation 
• 
CT/MRI Scan  
• 
Tumor assessment and measurements  
• 
Assess subject dosing compliance 
• 
Administration of megestrol acetate 
• 
Collect completed patient diary(ies) and issue new diary(ies) 
• 
Collect any empty bottle(s) of megestrol acetate  
Visit TP1-EXT (Week +12, ± 3 days) 
This treatment extension and visit is only for those subjects assessed to have disease 
control at Visit -1. 
• 
Concomitant medication review 
• 
Physical exam 
• 
Vital signs 
• 
Weight 
• 
Performance status 

 
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• 
CBC with differential, platelets 
• 
Serum chemistry 
• 
eGFR 
• 
ECG  
• 
AE evaluation 
• 
CT/MRI Scan  
• 
Tumor assessment and measurements 
• 
Assess subject dosing compliance 
• 
Administration of megestrol acetate 
• 
Collect completed patient diary(ies) and issue new diary(ies) 
• 
Collect any empty bottle(s) of megestrol acetate 
 
Subjects determined  to have disease control (SD, PR or CR) confirmed by tumor 
assessment after 24 weeks in Treatment Period 1, will be ineligible to enter Treatment 
Period 2.  The subject will be withdrawn from the study treatment and return for the End 
of Study Visit within 2 weeks to be discontinued from the study. 
 
END OF STUDY VISIT (2 weeks after TP1-EXT, +/- 7 days) 
For subjects who discontinue during TP1 for any reason (refer to Section 3.6) and those 
assessed to have disease control at Visit TP1-EXT: 
Subjects to be discontinued from TP1 should complete the EOS as soon as withdrawal 
is determined. 
Subjects assessed to have disease control at TP1-EXT should attend the EOS within 2 
weeks of TP1-EXT Visit. 
Subjects should continue their megestrol acetate dosing until the EOS unless the Inves-
tigator determines this is contraindicated. 
• 
Concomitant medication review 
• 
Physical exam 
• 
Vital signs 
• 
Weight 
• 
Performance status 
• 
CBC with differential, platelets 
• 
Serum chemistry 
• 
eGFR 
• 
Urinalysis 
• 
Urine Pregnancy Test (for women of childbearing potential) 
• 
ECG  
• 
AE evaluation 
• 
Collect any outstanding patient diaries 
• 
Collect all remaining megestrol acetate supplies  

 
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Subjects determined to have PrR negative status and subjects with documented 
disease progression after completing Treatment Period 1, will be eligible to enter 
Treatment Period 2.   
Treatment Period 2 
Visit 1, Day 0 (+/- 3 days) (Combination Treatment Start) 
• 
Eligibility criteria 
• 
Concomitant medication review 
• 
Physical exam 
• 
Vital signs 
• 
Weight 
• 
Performance status 
• 
CBC with differential, platelets 
• 
Serum chemistry 
• 
eGFR 
• 
ECG (before administration of Sodium Cridanimod and megestrol acetate, and 15, 
60, 120, and 360 (± 5) minutes after administration of Sodium Cridanimod) 
• 
For optional PK Sub-Study Participants: 
o 
Collection of blood samples for optional PK sub-study, at 10 timepoints: 0 min 
(before administration of Sodium Cridanimod and megestrol acetate), and 15 
min, 30 min, 45 min, 60 min, 90 min, 2 hr, 3 hr, 4 hr, and 6 hr (all times +/- 2 
minutes) after administration.  Note additional PK draws below** 
• 
AE evaluation 
• 
Assess subject dosing compliance 
• 
Collect completed patient diaries and remaining megestrol acetate for subjects 
completing Treatment Period 1 
• 
Issue patient diaries 
• 
Dispense supply of megestrol acetate  
• 
Administration of megestrol acetate  
• 
First administration of Sodium Cridanimod – The subject’s condition will be 
monitored closely for a one-hour period after this first administration. 
** Days 3, 7, and 10 for optional PK Sub-Study Participants: 
Blood samples will be taken on Days 3, 7 and 10 (before administration of Sodium 
Cridanimod and megestrol acetate).  
Visits 2, 6, 8, and 12 (Weeks 4, 20, 28, and 44; all ± 3 days) 
• 
Concomitant medication review 
• 
Vital signs 
• 
CBC with differential, platelets 
• 
Serum chemistry 
• 
eGFR 
• 
ECG 

 
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• 
AE evaluation 
• 
Assess subject dosing compliance 
• 
Collect completed patient diaries and issue new diaries 
• 
Collect any empty bottle(s) of megestrol acetate and dispense new supply 
• 
Continued dosing of Sodium Cridanimod and megestrol acetate 
 
Visit 3 (Week 8, ± 3 days) 
• 
Concomitant medication review 
• 
Physical exam 
• 
Vital signs 
• 
Weight 
• 
Performance status 
• 
CBC with differential, platelets 
• 
Serum chemistry 
• 
eGFR 
• 
ECG (before administration of Sodium Cridanimod and megestrol acetate, and 15, 
60, 120, and 360 (± 5) minutes after administration of Sodium Cridanimod) 
• 
For optional PK Sub-Study Participants: 
o 
Collection of Day 56 blood sample for optional PK sub-study (before 
administration of Sodium Cridanimod and megestrol acetate) 
• 
AE evaluation 
• 
Assess subject dosing compliance 
• 
Collect completed patient diaries and issue new diaries 
• 
Collect any empty bottle(s) of megestrol acetate and dispense new supply 
• 
Continued dosing of Sodium Cridanimod and megestrol acetate 
 
Visits 4 and 10 (Weeks 12 and 36; both ± 3 days) 
• 
Concomitant medication review 
• 
Vital signs 
• 
CBC with differential, platelets 
• 
Serum chemistry 
• 
eGFR 
• 
ECG 
• 
Visit 4 only - for optional PK Sub-Study Participants: 
o 
Collection of Day 84 blood sample for optional PK sub-study (before 
administration of Sodium Cridanimod and megestrol acetate) at Visit 4 only.  
Does not occur at Visit 10. 
• 
CT/MRI Scan  
• 
Tumor assessment and measurements 
• 
AE evaluation 
• 
Assess subject dosing compliance 
• 
Collect completed patient diaries and issue new diaries 
• 
Collect any empty bottle(s) of megestrol acetate and dispense new supply 

 
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• 
Continued dosing of Sodium Cridanimod and megestrol acetate 
 
Visits 5, 9, and 11 (Weeks 16, 32, and 40; all ± 3 days) 
• 
Concomitant medication review 
• 
Physical exam 
• 
Vital signs 
• 
Weight 
• 
Performance status 
• 
CBC with differential, platelets 
• 
Serum chemistry 
• 
eGFR 
• 
ECG 
• 
AE evaluation 
• 
Assess subject dosing compliance 
• 
Collect completed patient diaries and issue new diaries 
• 
Collect any empty bottle(s) of megestrol acetate and dispense new supply 
• 
Continued dosing of Sodium Cridanimod and megestrol acetate 
 
Visit 7 (Week 24, ± 3 days) 
• 
Concomitant medication review 
• 
Physical exam 
• 
Vital signs 
• 
Weight 
• 
Performance status 
• 
CBC with differential, platelets 
• 
Serum chemistry 
• 
eGFR 
• 
Urinalysis 
• 
Urine Pregnancy Test  (for women of childbearing potential) 
• 
ECG 
• 
CT/MRI Scan   
• 
Tumor assessment and measurements 
• 
AE evaluation 
• 
Assess subject dosing compliance 
• 
Collect completed patient diaries and issue new diaries 
• 
Collect any empty bottle(s) of megestrol acetate and dispense new supply 
• 
Continued dosing of Sodium Cridanimod and megestrol acetate 
 
Beginning with Visit 13 (Week 48), study visits will occur every 12 weeks instead 
of every 4 weeks. 
 
Visit 13, 14, 15, and continuing every 12 weeks until disease progression or 
other reason for withdrawal* (Weeks 48, 60, 72 etc.; all ± 7 days) 
• 
Concomitant medication review 

 
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• 
Physical exam 
• 
Vital signs 
• 
Weight 
• 
Performance status 
• 
CBC with differential, platelets 
• 
Serum chemistry 
• 
eGFR 
• 
Urinalysis 
• 
ECG  
• 
CT/MRI Scan  
• 
Tumor assessment and measurements 
• 
AE evaluation 
• 
Assess subject dosing compliance 
• 
Collect completed patient diaries and issue new diaries 
• 
Collect any empty bottle(s) of megestrol acetate and dispense new supply 
• 
Continued dosing of Sodium Cridanimod and megestrol acetate 
 
* Subjects continue administration of both Sodium Cridanimod and megestrol acetate 
until documented disease progression. If subjects have no evidence of progressive 
disease at Visit 13, they continue treatment as before, with visits to the Study Site 
continuing every 12 weeks thereafter until disease progression. At the visit where 
disease progression is documented, a new patient diary is not issued and no 
megestrol acetate is dispensed. 
 
Subjects who discontinue from the study during Treatment Period 2 for reasons other 
than disease progression will enter the Follow-up Period and return for the Safety 
Follow-up Visit.   
5.4.3. 
Follow-up Period (Subjects participating in Treatment Period 2 only) 
Safety Follow-up Visit (Four [4] weeks following the last treatment of Sodium 
Cridanimod, ± 3 days) 
• 
Concomitant medication review 
• 
Physical exam 
• 
Vital signs 
• 
Weight 
• 
Performance status 
• 
CBC with differential, platelets 
• 
Serum chemistry 
• 
eGFR 
• 
Urinalysis 
• 
Urine Pregnancy Test (for women of childbearing potential) 
• 
ECG  
• 
AE evaluation 
• 
CT/MRI Scan  

 
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• 
Tumor assessment and measurements should be obtained whenever possible for 
subjects discontinuing for reasons other than disease progression (unless a scan 
has been done within 4 weeks of withdrawal). 
• 
Collect any outstanding patient diaries 
• 
Collect all remaining megestrol acetate supplies 
 
Overall Survival Assessment (for 12 months after discontinuation of Treatment 
Period 2) 
• 
Confirm survival status of subject via telephone, personal contact or through clinic 
records once, at the end of the 12 month period. No Study Visits are required.  
This outcome is to be recorded in the eCRF. 
5.5. Efficacy Assessments 
5.5.1. 
Visual Tumor Examination 
The subject will undergo a clinical disease assessment for all palpable or visible lesions at the 
Screening Visit, and at Visits -1, TP1-EXT, and every 12 weeks in Treatment Period 2 to 
correlate with radiologic assessments. 
5.5.2. 
Tumor Imaging and Measurement (CT/MRI) 
Radiologic imaging with assessment and measurement of disease (CT or MRI scan of chest, 
abdomen, and pelvis) will be performed at the Screening, during Treatment Period 1 following 12 
weeks of treatment (at Visit -1), and if disease control is achieved, after an additional 12 weeks 
of treatment (at Visit TP1-EXT), during Treatment Period 2 every 12 weeks (± 7 day window) 
until disease progression is documented. 
In subjects with an objective response during Treatment Period 2, an additional radiologic 
assessment will be performed at least 4 weeks later to confirm the presence of an objective 
response. Response criteria is further outlined in Section 5.5. 
Radiographic imaging may also be performed at any point during the trial the Investigator 
determines this is indicated.  If disease progression is observed at an unscheduled scan during 
TP1, the subject is eligible to enter TP2 if she has received > 4 weeks of treatment, otherwise 
the subject must return for an End of Study Visit and be discontinued from the trial. If disease 
progression is observed at an unscheduled scan during TP2, the subject must be withdrawn 
from treatment, enter the Follow-up Period and return for the Safety Follow-up Visit.  An 
Unscheduled scan eCRF is to be completed. 
5.5.3. 
Gynecologic Oncology Group (GOG) Performance Status  
A subject will be assigned a GOG Performance Status at the Screening Visit and at Visits -3, -2, 
-1, TP1-EXT, EOS, 1, 3, 5, 7, 9, 11, 13, all subsequent quarterly Study Visits, and at the Safety 
Follow-up Visit, according to the following table: 

 
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Table 9. Performance Status Criteria 
Gynecologic Oncology Group (GOG) Status Scale 
GOG 
Score 
Descriptions 
0  
Fully active, unrestricted activities of daily living. 
1  
Ambulatory, but restricted in strenuous activity. 
2  
Ambulatory, and capable of self care. Unable to work. Out of bed for greater than 50% of waking hours. 
3  
Limited self care, or confined to bed or chair 50% of waking hours. Needs special assistance. 
4  
Completely disabled, and no self care. 
5  
Dead. 
5.6. Assessment of Response 
Tumor measurements will be collected by CT or MRI scan, as noted in Section 5.5.2.  CT or MRI scan 
of chest, abdomen, and pelvis are appropriate, but all scans for an individual subject must use the 
same procedure as was performed at baseline. Conventional CT and MRI should be performed with 
contiguous cuts of 10mm or less in slice thickness. Spiral CT should be performed by use of a 5 mm 
contiguous reconstruction algorithm. Ultrasound should not be used for measurement. Clinically 
detected lesions will only be considered measurable if they are superficial (e.g. skin nodules and 
palpable lymph nodes). For skin lesions, documentation by color photography, including a tool to 
estimate size of the lesion, is recommended. Photographs should be retained with all other study 
documents at the study site. 
In subjects with an objective response (as defined below), an additional CT/MRI scan and tumor 
assessment will be performed at least four weeks later to confirm the presence of objective response. 
If a subject discontinues Treatment Period 2 for any reason other than disease progression (i.e. 
intolerable AE), every reasonable effort should be taken to encourage subjects to continue receiving 
regular CT/MRI scans and tumor assessments until disease progression is documented, with the date 
of disease progression still recorded in the eCRF. 
5.6.1. 
Measurable Disease Definitions 
Important inclusion criteria for this trial include the presence of measurable disease with at least 
one target lesion to use for all disease assessments. 
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as >20 mm by chest x-ray or as >10 mm with CT or 
MRI scan, or calipers by clinical exam.  All tumor measurements must be recorded in millimeters 
(or decimal fractions of centimeters). For a lymph node to be considered pathologically enlarged 
and measurable, it must be >15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are not considered measurable unless there has been demonstrated 
progression in the lesion before study entry. 

 
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Non-measurable lesions are all other lesions, including small lesions (longest diameter <10 mm 
or pathological lymph nodes with ≥10 to <15 mm short axis), are considered non-measurable 
disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed 
by CT or MRI), are considered as non-measurable. 
5.6.2. 
Definitions of Response 
Target Lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline. Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, and in addition should be 
those that lend themselves to reproducible repeated measurements. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum of diameters.  If lymph nodes are to 
be included in the sum, then only the short axis is added into the sum. 
Table 10. Target Lesion Evaluation 
Response 
Definition 
Complete Response 
(CR) 
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis <10 
mm  
Partial Response 
(PR) 
At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters 
Progressive Disease 
(PD) 
At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to the 
relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. The appearance of one or more 
new lesions is also considered progression. 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters 
while on study. 
 
Non-Target Lesions: All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence or 
absence of each should be noted throughout the study. 
 
Table 11. Non-Target Lesion Evaluation 
Response 
Definition 
Complete Response 
(CR) 
Disappearance of all extranodal non-target lesions.   
All lymph nodes must be non-pathological in size (<10 mm short axis). 
Non CR/Non PD 
Persistence of one or more non-target lesion(s)  

 
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Progressive Disease 
(PD) 
Unequivocal progression of existing non-target lesions.  The 
appearance of one or more new lesions is also considered progression 
Symptomatic Deterioration: Subjects with a global deterioration of health status requiring 
discontinuation of treatment in Treatment Period 2 without objective evidence of disease 
progression at that time should be classified as having symptomatic deterioration. Reasonable 
efforts should be taken to obtain radiographic evidence to confirm disease progression. Subjects 
experiencing symptomatic deterioration during Treatment Period 1 are ineligible to enter 
Treatment Period 2 (as they do not meet the inclusion criteria requiring radiographic evidence of 
progression). 
The baseline sum of diameters (from the Screening Visit) will be used as reference to further 
characterize disease control in the measurable dimension of the disease to determine the 
eligibility to continue participation in Treatment Period 2 of the study. From that point onward, the 
scan that led to those subjects’ termination of Treatment Period 1 and eligibility to enter 
Treatment Period 2 will serve as a subject’s new “baseline” measurements, with that sum of 
diameters used as reference to characterize the objective tumor response.  CR and PR are 
defined as Objective Responses and must be confirmed by repeat assessment performed at 
least four weeks after the criteria for response are first met. 
Table 12. Evaluation of Time Point Response: Patients with target (+/– non-target) disease* 
Target Lesions
Non Target Lesions
New Lesions
Overall 
Response 
Confirmation 
Scan  
(Treatment 
Period 2 only) 
CR 
CR 
No 
CR 
Yes 
CR 
Non CR/Non PD 
No 
PR 
Yes 
CR 
Not Evaluated 
No 
PR 
Yes 
PR 
Non CR/Non PD/Not 
Evaluated 
No 
PR 
Yes 
SD 
Non CR/Non PD 
No 
SD 
No 
PD 
Any 
Yes or No 
PD 
No 
Any 
PD 
Yes or No 
PD 
No 
Any 
Any 
Yes 
PD 
No 
*Derived from New Response Evaluation Criteria in Solid Tumours: Revised RECIST guideline (version 1.1), Table 1, 2 
& 3 
5.6.3. 
Evaluations of a Subject’s Best Overall Response 
The best overall response is the best response recorded from the start of Treatment Period 2 
until disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The subject’s best response assignment 
will depend on the achievement of both measurement and confirmation criteria.  
Table 13.  Best overall response when confirmation of CR and PR required*  

 
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Overall Response First 
Time Point 
Overall Response 
Subsequent Time Point
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PR 
CR 
SD 
SD provided minimum criteria for SD duration 
met, otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration 
met, otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD duration 
met, otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration 
met, otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration 
met, otherwise, NE 
*Derived from New Response Evaluation Criteria in Solid Tumours: Revised RECIST guideline (version 1.1), Table 5 
First Documentation of Response: The time between the initiation of Treatment Period 2 and the 
first documentation of PR or CR. 
Confirmation of Response: To be assigned a status of CR or PR, tumor measurements must be 
confirmed by repeat assessment performed at least four weeks after the criteria for response are 
first met. 
Duration of Response: The period of time from the disease assessment at which measurement 
criteria are first met for CR or PR (whichever status is recorded first) until the first date that 
recurrent or progressive disease is objectively documented. 
Duration of Complete Response (CR): The period of time from the disease assessment at which 
criteria for CR are met until the first date that recurrent disease is objectively documented. 
Duration of Stable Disease: The time from the initiation of combination therapy on Study Visit 1 
in Treatment Period 2 until the criteria for disease progression are first met. 
Disease Control: Disease control is defined as all Best Overall Responses that are not 
progressive disease (i.e. SD, PR or CR). 
 
5.7. Safety Assessments 
5.7.1. 
Concomitant Medication 
Concomitant medication is defined as any medication, other than the investigational medicinal 
product (Sodium Cridanimod) and megestrol acetate, taken at any point in the duration from the 
Screening Visit until the End of Study Visit or the Safety Follow-up Visit. This includes all 
prescription medications, over-the-counter medications, and herbal remedies. All concomitant 
medications will be recorded. 

 
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5.7.2. 
Vital Signs  
The subject will undergo an assessment of vital signs (systolic and diastolic blood pressure, 
heart rate and body temperature) after 5 minutes in a supine position at the Screening Visit, at all 
Study Visits, at the End of Study Visit, and at the Safety Follow-up Visit. 
5.7.3. 
Laboratory Assessments 
Hematology, biochemistry, and urinalysis samples will be analyzed by the local laboratory using 
standard methods. 
5.7.3.1. 
Hematology 
Blood samples (5 mL) will be taken at the Screening Visit, at each Study Visit, at the End 
of Study Visit, and at the Safety Follow-up Visit and used for routine hematology 
analysis. 
Hematology profile will include: 
• 
Hemoglobin value 
• 
Hematocrit 
• 
Mean corpuscular volume (MCV) 
• 
Mean corpuscular hemoglobin concentration (MCHC) 
• 
Erythrocytes 
• 
Leucocytes  
• 
Differential leukocyte count (neutrophils, lymphocytes, monocytes, eosinophils 
and basophils)  
• 
Platelet count 
5.7.3.2. 
Serum Chemistry 
Blood samples (5 mL) will be taken at the Screening Visit, at each Study Visit, at the End 
of Study Visit, and at the Safety Follow-up Visit and used for routine serum chemistry 
analysis. 
Chemistry profile will include: 
• 
Phosphate 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Calcium 
• 
Bicarbonate 
• 
Creatinine 
• 
Creatine kinase 
• 
Glucose 
• 
Blood urea nitrogen (BUN) 
• 
Total proteins 
• 
Albumin 

 
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• 
Total bilirubin 
• 
Alkaline phosphatase 
• 
Lactate dehydrogenase (LDH) 
• 
Serum glutamic oxaloacetic transaminase (SGOT) / Aspartate aminotransferase 
(AST) 
• 
Serum glutamic pyruvic transaminase (SGPT) / Alanine aminotransferase (ALT) 
Estimated Glomerular Filtration Rate (eGFR) will be calculated based on blood 
creatinine levels and subject demographics using the CKD Epidemiology Collaboration 
(CKD-EPI method14. 
5.7.3.3. 
Urinalysis 
Urine samples are taken at the Screening Visit, at the End of Study Visit, at Visit 7, at 
Visit 13 and every 12 weeks thereafter until disease progression, and at the Safety 
Follow-up Visit. 
Urine analysis will include: 
• 
Blood 
• 
Protein 
• 
Glucose 
• 
Ketones 
• 
pH 
5.7.4. 
Pregnancy Test 
Pregnancy tests are applicable to all subjects of childbearing potential (i.e. excluding those who 
are anatomically sterile or are post-menopausal). A serum pregnancy test (measuring β-human 
chorionic gonadotropin [β-hCG]) will be performed at the Screening Visit, and a urine pregnancy 
test will be performed at Visit 7 at the End of Study Visit, and at the Safety Follow-up Visit. 
5.7.5. 
Physical Examination 
The subject will undergo an evaluation of all major body systems, including the measurement of 
height and weight. Physical examinations will be performed at the Screening Visit and at 
Visits -3, -2, -1, TP1-EXT, EOS, 1, 3, 5, 7, 9, 11, 13, at all subsequent quarterly Study Visits, and 
at the Safety Follow-up Visit. 
5.7.6. 
Electrocardiogram 
A 12-lead Electrocardiogram (ECG) will be performed to evaluate potential study drug-induced 
QT prolongation potential at the Screening Visit, at all Study Visits, at the End of Study Visit, and 
at the Safety Follow-up Visit. At Visits 1 and 3, ECG will be performed 5 times: before 
administration of both Sodium Cridanimod and megestrol acetate, and at 15, 60, 120, and 360 (± 
5) minutes after administration of Sodium Cridanimod. ECGs at all other visits will be performed 
only once, prior to administration of both Sodium Cridanimod and megestrol acetate. 

 
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For all ECGs performed after the first dose of Sodium Cridanimod, any clinically significant 
changes compared with the ECG recorded at the Screening Visit must be reported as an AE. All 
ECG intervals (QT, QTcB, QTcF, PR, QRS, and RR) will be reported in the eCRF. 
5.7.7. 
Patient Diary 
At all visits following the Screening Visit, the subject will be provided with Patient Diaries and 
asked to record their daily doses of megestrol acetate (including those taken in clinic during a 
study visit).  In addition, subjects are to record any AEs and concomitant medications in the 
diary.  Diaries will be completed by the subjects until they exit the study at the End of Study Visit 
or the Safety Follow-up Visit.  Subjects will be instructed to return their completed diaries at each 
Study Visit and new diaries will be provided to the subject. 
5.8. Optional Sub-Study Procedures 
To address an important translational objective, subjects will have the ability to consent to participate in 
an optional sub-study. Participation in this sub-study is completely voluntary and will not affect the 
subject’s ability to participate in the study. Participation in this study will undergo additional study 
procedures as outlined below. 
5.8.1. 
Optional Pharmacokinetic (PK) Sub-Study 
An important objective of this study is to investigate the possible pharmacokinetics of megestrol 
acetate when administered alone (Treatment Period 1), and the pharmacokinetic drug-drug 
interactions of Sodium Cridanimod and megestrol acetate when administered together 
(Treatment Period 2). To accomplish this objective, certain subjects will be enrolled to participate 
in an optional Pharmacokinetic Sub-Study.  
For these subjects, additional blood samples will be taken as follows: 
• 
Treatment Period 1:  Study Visit -3, before administration of megestrol acetate, and 1, 2, 3, 
4, 6, 24, 48, 72 and 96 hours (all times +/- 2 minutes) after administration.  Subjects who 
are PrR negative will not participate in this portion of the PK Sub-Study. 
• 
Treatment Period 2:  Study Visit 1, before administration of both Sodium Cridanimod and 
megestrol acetate and at 15, 30, 45, 60 and 90 minutes, 2, 3, 4 and 6 hours (all times +/- 2 
minutes) after administration. Blood samples will additionally be taken on Days 3, 7, 10, 56 
(Visit 3) and Day 84 (Visit 4) prior to the administration of both Sodium Cridanimod and 
megestrol acetate. Administration of the study drugs should be timed as close as possible on 
PK days, preferably within 5 minutes or less.  Timing of the post dose PK blood sample 
collection should be based on the Sodium Cridanimod dose. 
Blood samples will be analyzed in a central laboratory using standard analysis methods. 
5.9. Adverse Events and Other Safety Aspects 
5.9.1. 
Definition of Adverse Events  
An AE is any untoward medical occurrence in a subject administered a medicinal product and 
which does not necessarily have to have a causal relationship with treatment in Treatment Period 
1, 2 through either the End of Study Visit or the Safety Follow-up Visit.  An AE can therefore be 
any unfavorable and unintended sign (for example, an abnormal laboratory finding), symptom, or 

 
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disease temporally associated with the use of a medicinal product, whether or not considered 
related to this medicinal product. 
For the purposes of this protocol, an AE is any undesirable sign(s), symptom(s) or worsening of 
pre-existing condition(s) occurring after the signing of the informed consent through the final study 
visit, even if the event is not considered to be related to the study drug. No AEs information will be 
collected following the End of Study Visit/Safety Follow-up Visit. 
AEs do not include the following: 
• 
The disease being studied, or the expected progression, signs or symptoms 
(including laboratory values) of the disease being studied, unless it is more severe 
than expected for the subject’s condition.  Disease progression or symptoms related 
to disease progression will not be considered AEs. 
• 
Pre-existing disease or medical conditions that does not worsen from those reported 
at Screening. 
• 
Hospitalizations for elective surgery unless the event meets other criteria as an SAE 
such as “prolonged hospitalization”. 
• 
Hospital admissions for social or convenience reasons where an AE does not occur.   
• 
Medical or surgical procedures such as surgeries and transfusions.  These are 
treatments for an AE resulting in the procedure.  The underlying AE should be 
reported as the event, not the procedure.  
• 
Elective treatment of a pre-existing disease or medical condition that did not worsen 
or result in AEs, e.g., hospitalization for chemotherapy for cancer. 
• 
Overdose of either study drug or any concomitant medication without any signs or 
symptoms.  
Intercurrent illnesses or injuries should be regarded as AEs.  Abnormal results of diagnostic 
procedures are considered to be AEs if the abnormality: 
• 
is considered by the Investigator to be of clinical significance 
• 
results in study withdrawal 
• 
is associated with clinical signs or symptoms 
• 
leads to additional treatment or to further diagnostic tests 
An AE is “unexpected” when the nature, severity, specificity, or outcome is not consistent with the 
term or description used in protocol related documents including the Investigator brochure, product 
labeling (e.g. Package Insert or Summary of Product Characteristics), protocol and IEC/IRB 
approved informed consent form.  If an Investigator is uncertain whether an AE is expected or 
unexpected, the AE should be reported as unexpected. 
The outcome of each AE should be assessed as follows:  
• 
Fatal: Subject has died due to AE 
• 
Not Recovered/Not Resolved: AE is ongoing 
• 
Recovered/Resolved: AE is no longer present  
• 
Recovered/Resolved with sequelae: AE has resolved but the subject retains a 
condition that is the consequence of the AE  

 
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• 
Recovered/Resolving: AE is in the process of recovering 
• 
Unknown: Outcome of the AE is not known because the subject did not return for 
follow-up and attempts to obtain follow-up were unsuccessful 
The Investigator will assess subjects for AEs at each study visit through the End of Study 
Visit/Safety Follow-up Visit.  All AEs observed or reported after the subject has provided informed 
consent must be recorded in the source data and reported on the eCRF regardless of causal 
relationship.  The nature of each AE, date of onset, outcome, severity, actions taken with respect 
to dosage, and relationship to study drug should be assessed and recorded.  Any changes to 
study drug dosing or any medical treatment should be recorded in the source and appropriate 
eCRFs.  AEs documented at a previous assessment as ‘ongoing’ should be reviewed at 
subsequent visits as necessary until resolved. 
All related signs, symptoms, and abnormal diagnostic procedures results should be grouped as a 
diagnosis whenever possible.  All AEs will be assessed for severity, seriousness and causality by 
the Investigator.  
AEs that do not meet the criteria for expedited reporting will be documented in the eCRF and 
reported in the final clinical study report. 
5.9.2. 
Definition of Serious Adverse Events  
An SAE is defined as any untoward medical occurrence or effect that, at any dose: 
• 
Results in death;  
• 
Is life-threatening*; 
• 
Requires hospitalization or prolongation of hospitalization; 
• 
Results in persistent or significant disability or incapacity; 
• 
Is a congenital abnormality or birth defect; 
• 
Other medically important event 
Medical judgment should be exercised in deciding whether an AE/reaction is serious in other 
situations.  Important AEs/reactions that are not immediately life-threatening, or do not result in 
death or hospitalization but may jeopardize a subject, or may require intervention to prevent one 
of the other outcomes listed in the definition above should also be considered serious. 
* “Life-threatening” in the definition of “serious” refers to an event in which the subject was at risk 
of death at the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe. 
 
 

 
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5.9.3. 
Criteria for Causal Relationship 
Table 14.  The causality of each AE should be assessed using one of the following terms: 
Causal Relationship* 
to the Study Drug 
Criteria for Causal Relationship 
Related 
AE occurring in a plausible time relationship to drug administration, and 
which cannot be explained by concurrent disease or other drugs or 
chemicals.  
Possibly Related  
AE occurring with a reasonable time sequence to administration of the drug, 
unlikely to be attributed to concurrent disease or other drugs or chemicals. 
Unlikely Related  
AE occurring with a reasonable time sequence to administration of the drug, 
but which could also be explained by concurrent disease or other drugs or 
chemicals. 
Not Related 
AE with a temporal relationship to drug administration which makes a causal 
relationship improbable, and in which other drugs, chemicals or underlying 
disease provide plausible explanations. 
*Definitions with basis in Clinical Data Acquisition Standards Harmonization (CDASH), ICH E2B. 
For data analysis and SAE reporting purposes, any AEs classified as ‘unlikely related” will be 
regarded as ‘not related’ to study drug.  AEs classified as ‘possibly related” will be regarded as 
‘related’ to the study drug.  
5.9.4. 
Criteria for Defining the Severity of an Adverse Event 
Table 15.  The severity of all AEs should be graded according to the NCI-CTCAE Version 4: 
Grade 
Assessment Standard 
1 – Mild 
Does not hamper daily activities 
2 – Moderate 
Hampers daily activities 
3 – Severe 
Makes daily activities impossible 
4 – Life-Threatening 
Imminent risk of death 
5 – Death 
Death 
5.9.5. 
Reporting of Serious Adverse Events (SAEs) 
AEs meeting the criteria as an SAE must be reported to ProductLife Pharmacovigilance within 24 
hours of becoming aware of its occurrence even if the SAE does not appear to be study drug-
related.    An SAE Form and any related eCRFs must also be completed by the Investigator and 
faxed or emailed to ProductLife Pharmacovigilance within 24 hours:    
 
SAFETY REPORTING Contact:  ProductLife Pharmacovigilance 
• 
Email:  safety@productlife-group.com 
• 
Fax: 1-800-963-0353 
Within the following 48 hours, the Investigator shall provide further any additional information 
regarding the SAE and a written narrative of the event.  Follow-up including additional information, 

 
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complications or worsening of the initial SAE must be reported as follow-up to the original episode 
within 24 hours of the Investigator receiving the information.  Any SAEs experienced up to 60 
days after last administration of study drug should be reported if the Investigator suspects a 
causal relationship to the study drug.  Deaths or congenital abnormalities brought to the attention 
of the Investigator at any time after administration of study drug and considered by the 
Investigator to be possibly related to study drug, should be reported to the Sponsor.  
The Investigator must also notify the reviewing IEC/IRB in writing as soon as possible but no later 
than 72 hours of knowledge of an SAE.  Documentation of IEC/IRB notification and receipt will be 
kept in the Investigator’s study file. 
Expedited regulatory reports will be submitted by Xenetic or designee to the regulatory authorities 
in accordance with specific country requirements. 
5.9.6. 
Reporting of Deaths 
The death of any subject during the study, regardless of the cause, must be reported within 24 
hours of the Investigator or the study site personnel becoming aware of the occurrence. 
Death cases are to be captured in the SAE and Mortality pages of the eCRF. If an autopsy is 
performed, the report must also be provided. 
Depending on country specific requirements, death cases will be submitted to the appropriate 
Regulatory Authorities, as well as IEC/IRB(s), as applicable. 
5.9.7. 
Procedure in Case of Pregnancy 
If a subject becomes pregnant at any time during the trial, the subject must be withdrawn from the 
trial and Safety Follow-up procedures should be completed.  The Investigator should report the 
pregnancy to ProductLife Pharmacovigilance within 24 hours of becoming aware of event.    
The subject should be followed by the Investigator until completion of the pregnancy.  If the 
pregnancy ends for any reason before the anticipated date, the Investigator should notify 
ProductLife Pharmacovigilance. 
At the completion of the pregnancy, the Investigator will document the outcome of the pregnancy.  
If the outcome of the pregnancy meets the criteria for immediate classification as an SAE (i.e., 
postpartum complication, spontaneous abortion, stillbirth, neonatal death, or congenital anomaly), 
the Investigator should follow the procedures for notification of SAEs. 
6. TERMINATION OF THE CLINICAL STUDY 
The Sponsor reserves the right to discontinue the study for safety, ethical or administrative reasons. 
Any concerned regulatory authorities also have the authority to discontinue this trial. 
All Investigators will be notified in writing, outlining the reasons for the discontinuation of the study at their site.  
Instructions will be provided if assessments beyond the regular per protocol procedures should be necessary. 
If a study is prematurely terminated, the Sponsor will promptly inform the IEC/IRB and competent authorities 
of the termination and its reason(s). 

 
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7. 
STATISTICAL METHODOLOGY 
7.1. Sample Size 
The primary objective of the study is to evaluate the efficacy of the study drug by the frequency of 
subjects with overall disease control (including SD, PR, and CR). 
The null hypothesis assumes an historical disease control rate of <5%, given that these subjects have 
already failed progestin therapy. A clinically significant difference is predefined as a 15% increase (i.e. 
disease control rate of 20%). Using the Fleming’s single stage procedure (in which a predetermined 
number of patients is recruited to the study and a decision about activity is obtained from the number 
of responses (including SD, PR, or CR) amongst these patients) with the probabilities of type I and 
type II errors of 5% (one-sided) and 10%, respectively, approximately 40 subjects are planned to be 
enrolled to Treatment Period 2. It is estimated that approximately 20-25% of subjects will be classified 
as PrR negative and go directly into Treatment Period 2.  This group will represent 14-16 of the 
Treatment Period 2 subjects. The rate of subjects who will have progressive disease following 
treatment with megestrol acetate in Treatment Period 1 and then move on to Treatment Period 2 is 
estimated at 55-60%.  These subjects will represent 30-32 of the Treatment Period 2 subjects 
(estimating that approximately 24-25 subjects treated in Treatment Period 1 will not exhibit progressive 
disease and will not move into Treatment Period 2.)  Estimating the rate of subjects who will be 
unavailable for disease assessment for various reasons at10-15%, it is planned to enroll 72 total 
subjects.  An estimated 20% screen failure rate will require up to 90 screened patients to allow for 
enrollment of 72 subjects. 
7.2. Analysis Sets 
7.2.1. 
Safety Population 
The Safety Population will consist of all subjects who receive at least one full or partial dose of 
study treatment (all treated subjects) in Treatment Period 2. This population will be used for all 
safety reporting. Safety data will be reported separately for subjects in Treatment Period 1 who 
do not go on to Treatment Period 2, and for those subjects in Treatment Period 1 who are 
treated in both periods. 
7.2.2. 
Full Analysis Set (FAS) 
The FAS will consist of all subjects treated in Period 2 who either undergo a CT or MRI scan with 
tumor assessment at Visit 4 (i.e. they have not discontinued treatment prior to Visit 4) or those 
who have discontinued Treatment Period 2 prior to Visit 4 solely due to documented disease 
progression. This population will be used for efficacy evaluation.  
7.2.3. 
Per Protocol Set (PPS) 
The Per Protocol Set will consist of all FAS subjects, excluding those for whom major protocol 
deviations have been identified. This population will be used for supportive analysis of the 
response rate and other efficacy parameters. 

 
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7.3. Demographics and Other Baseline Characteristics 
A descriptive analysis approach will be used to analyze all demographic and baseline 
characteristics and will be presented using appropriate summary statistics (mean, standard 
deviation, median, minimum, maximum, range, quintiles, frequency and percentage for 
categorical variables with 95% confidence limits etc., when appropriate). The Safety Population 
will be used to present all demographic and baseline characteristics. 
7.4. Analysis of Efficacy 
The Full Analysis Set will be used for all efficacy analysis. The Per Protocol Set will be used for 
supportive analysis of all efficacy parameters. 
7.4.1. 
Analysis of Primary Objective 
The primary objective of this study is to evaluate the efficacy of the study drug by the frequency 
of subjects with overall disease control (including SD, PR, and CR). 
The ODCR will be determined as the proportion of subjects who achieved SD, PR and CR 
during Treatment Period 2. The ODCR will be estimated and presented with the corresponding 
95% confidence interval. 
7.4.2. 
Analysis of Secondary and Translational Objectives 
The secondary efficacy objective is to assess the ORR, PFS, duration of Stable Disease, and 
OS. 
The Objective Response Rate (ORR) is defined as the proportion of subjects who achieved CR 
or PR during Treatment Period 2. The ORR will be estimated and presented with the 
corresponding 95% confidence interval. 
Progression-free Survival (PFS) is defined as the duration of time from initiation of Treatment 
Period 2 (Day 0) until disease progression or death from any cause, whichever occurs first. For 
the purpose of analysis of PFS, subjects with an unknown response will be censored. 
Duration of Stable Disease is defined as the duration of time from initiation of Treatment Period 2 
(Day 0) until the criteria for disease progression are first met. For the purpose of analysis of 
Duration of SD, subjects who die before documented progressive disease will be censored. 
Overall Survival (OS) is defined as the duration of time from initiation of Treatment Period 2 (Day 
0) until the subject’s death from any cause. For the purpose of analysis of OS, if a subject is alive 
at the date of last contact the subject will be censored at that date of contact. 
OS, Duration of Stable Disease, and OS will be analyzed by the Kaplan-Meier method, and the 
Kaplan-Meier survival curves will be plotted. 
 
 

 
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7.5. Analysis of Safety 
7.5.1. 
Adverse Events 
AEs developed after informed consent and before administration of the study drug will be rendered 
as AEs occurred before the treatment.  AEs developed after the first administration of the study 
drug will be rendered as AEs occurred during the treatment. 
Information about AEs will be coded with the use of medical dictionary MedDRA in the current 
revision.  The frequency of occurrence of AEs during the treatment will be calculated for each 
system organ class and each main diagnosis.  The information will be presented as absolute 
number of subjects with AE and relative frequency.  Summary data for the severity of AEs and 
their relationship with the study treatment will be presented for each system organ class and each 
main diagnosis. 
Summary data about withdrawal of subjects from the study due to the development of AEs will be 
presented for each system organ class and each main diagnosis. 
SAEs will be presented as listings and as summaries for each system organ class and each main 
diagnosis. 
7.5.2. 
Clinical Laboratory Evaluations 
Results of laboratory evaluations (hematology, serum chemistry, and urinalysis) will be presented 
as listings and summaries for each measurement point. Values of laboratory tests outside the 
normal range (i.e. abnormal values) will be determined based on each labs specification of 
normal ranges and will be indicated in listings. Shift tables for laboratory tests will contain 
information about change of distribution of values below, inside and outside of normal range from 
the screening period to the date of the End of Study Visit/Safety Follow-up Visit. 
7.5.3. 
Physical Examination 
Results of physical examinations will be presented for each measurement point. 
7.5.4. 
Vital Signs 
Vital signs (systolic and diastolic blood pressure, heart rate and body temperature) will be 
presented as a listings and summaries for each measurement point. Statistical significance of 
changes relative to baseline values will be analyzed with applicable statistical methods. 
7.5.5. 
Electrocardiogram  
Results of ECG (“normal”, “with clinically non-significant deviations from normal”, and “with 
clinically significant deviations from normal”) will be presented as listings and as summaries for 
each measurement point. 
ECG intervals (QT and QT intervals adjusted by an appropriate correction [QTcB and QTcF; 
Bazett and Fridericia], PR, QRS, and RR) will be summarized at each scheduled timepoint, 
along with mean change from baseline to each post treatment timepoint. 
ECG intervals (QTcB and QTcF; Bazett and Fridericia) recorded at Visits 1 and 3 will be 
presented both as analyses of central tendency and categorical analyses. 

 
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7.5.6. 
Gynecologic Oncology Group (GOG)  
Performance Status Results of GOG performance status assessment will be presented as 
listings and as summaries for each measurement point. 
7.6. Analysis of Pharmacokinetics 
For each subject, the following PK parameters after a single dose and multiple doses will be 
calculated, whenever possible, based on the plasma concentrations of Sodium Cridanimod and 
progestins, using non-compartmental methods:  
Table 16. Pharmacokinetics Analysis Parameters 
Cmax 
Maximum observed concentration. 
tmax 
Time to maximum concentration. 
AUC0-
t 
Area under the concentration-time curve from time 0 to the time of the last measurable concentration, 
calculated using the linear trapezoidal rule for increasing concentrations and the logarithmic rule for 
decreasing concentrations.  
AUC0-∞ 
Area under the concentration-time curve extrapolated to infinity, calculated using the formula:  
AUC00-∞ = AUC0-t + Ct/ λz 
where Ct is the last measurable concentration and λz is the apparent terminal elimination rate con-
stant. 
t1/2 
Apparent terminal elimination half-life (whenever possible), where  
t1/2 = (ln2)/ λz 
CL/F 
Total clearance for extravascular administration  
Vz/F 
Volume of distribution based on the terminal phase 
Other parameters may be calculated as appropriate. Obtained pharmacokinetics data will also be used 
as a part of data for population pharmacokinetics analysis, assessment of effect of body weight and 
body surface area on pharmacokinetics of study drug and evaluation the potential for a 
pharmacokinetic interaction between Sodium Cridanimod and progestins used in the study. 
Pharmacokinetic analysis will use actual times as recorded on the eCRF. 
7.7. Protocol Deviations 
Any violations of the inclusion or exclusion criteria or subject compliance outside of the 80-120% 
acceptable range will be considered major protocol violations. These (and any other) protocol 
deviations will be clearly documented in the eCRF. Subjects for whom major protocol deviations were 
recorded will not be included in the Per Protocol Set. 
7.8. Handling of Missing Data, Outliers, Visit Windows, and Other Information 
7.8.1. 
Missing Data 
Statistical analysis will be performed using available data only; missing values will not be 
imputed. 

 
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7.8.2. 
Visit Windows 
Each Study Visit has an acceptable window for when it must occur (see Section 5.4). Any visit 
that falls outside of the acceptable window must be clearly documented as a protocol deviation. 
Data collected at such a visit may still be used for analysis of all safety and efficacy objectives, 
using the date for when the data was collected (as recorded in the eCRF). 
8. 
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS 
8.1. Procedure for Clinical Study Quality Control 
8.1.1. 
Clinical Study Monitoring 
The study will be supervised by a monitor from the Sponsor or CRO.  The study monitor will 
contact the Investigator regularly to discuss the progress of the study and to check the study 
documents including the informed consent forms for completeness and consistency. 
It is understood that monitors, and any authorized personnel contracted to the Sponsor or CRO 
may contact and visit the Investigator, and that they will be allowed to inspect the various records 
of the study on request (eCRFs and other pertinent data), provided that subject confidentiality is 
maintained, and that the inspection is conducted in accordance with local regulations. 
It is the monitor’s responsibility to inspect the eCRFs at regular intervals throughout the study to 
verify adherence to the protocol, the completeness, accuracy and consistency of the data, and 
adherence to regulatory requirements and ICH GCP guidelines.   
The Investigator agrees to cooperate with the monitor to ensure that any problems detected 
during the course of these monitoring visits are resolved. 
8.1.2. 
Source Data 
Where source documents (such as laboratory reports, medical records, or ECG reports) or 
laboratory databases exist, all relevant data will be transcribed into the eCRF, transferred 
electronically to the study database, or entered into the study database directly from source 
documents. Where no source documents exist, data will be written directly into the eCRF 
The Investigator/institution will permit study-related monitoring, audits/inspections, IEC/IRB 
review and regulatory inspections to directly access source documents. 
8.1.3. 
Language 
eCRFs will be developed in the English language for all subjects at all study sites. All recordings 
in the eCRF will be in English.  Generic names for concomitant medications should be recorded 
in the eCRF wherever possible. All written material to be used by subjects must use vocabulary 
that is clearly understood and be in the language appropriate for the subjects participating at the 
study site. 
8.1.4. 
Data Collection 
All of the clinical data will be captured via a web-based electronic data capture (EDC) tool.  

 
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The Investigator site staff will enter and edit the data via a secure network with secure access 
features (i.e. username and password). A complete electronic audit trail will be maintained. The 
Investigator will approve the data using an electronic signature, and this approval is used to 
confirm the accuracy of the data recorded. 
eCRFs will be used for all subjects. The Investigator’s data will be accessible from the 
Investigator’s site throughout the trial. The eCRFs must be kept current to reflect subject status 
at each phase during the course of the trial. A screening number will identify the subjects on the 
eCRF. The Investigator must make a separate confidential record of personalized details (name 
and initials) on the subject identification log. All changes to data are done by the Investigator 
through the EDC system. If a change is necessary once the Investigator has no further access to 
the database, a request for change will be sent to the Investigator for confirmation of the change. 
It is the responsibility of the Principal Investigator of each site to ensure that all subject 
discontinuations or changes in study or other changes in subject health entered on the subject’s 
eCRF are also documented on the subject’s medical records. 
The eCRFs for any subject leaving the study should be completed at the time of the final visit or 
shortly thereafter. Data reported in the eCRFs that are transcribed from source documents must 
be consistent with the source documents or the discrepancies must be explained. 
All laboratory reports (if applicable) will be reviewed, signed and dated by the Investigator. 
8.1.5. 
Data Management 
Data management will be coordinated by the Sponsor in accordance with the standard operating 
procedures (SOPs) for data management.  All study specific processes and definitions will be 
documented by Data Management.  eCRF correction process will be referenced in the eCRF 
instructions.  Coding of medical terms will be performed using MedDRA. 
The study database will be soft-locked when all data that are specified in the study protocol to be 
collected have been received and cleaned.  It will be hard-locked when a data review meeting has 
been held, and all data related decisions have been made and reflected in the database. 
8.1.6. 
Protocol Deviations 
The Investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.  The Investigator should not implement any 
deviation from, or changes of, the protocol without the agreement by the Sponsor and prior review 
and documented approval/favorable opinion of the IEC/IRB of an amendment, except where 
necessary to eliminate an immediate hazard to trial subjects.  The Investigator must document all 
protocol deviations in the subject’s source documents and applicable eCRFs or deviation forms.  
The process for reporting deviations will be communicated to the site by the Sponsor.  For the 
purposes of this protocol, deviations requiring notification to Sponsor are defined as: 
• 
Subject entered into the study even though they did not satisfy entry criteria. 
• 
Subject who developed withdrawal criteria during the study and was not withdrawn. 
• 
Subject who received an incorrect dose. 

 
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• 
Subject who received excluded concomitant treatment as noted  
NOTE: Other deviations outside of the categories defined above that are required by the IEC/IRB 
in accordance with local requirements will be reported, as applicable. 
8.1.7. 
End of Trial 
The end of trial for all participating countries is defined as the date of the last subject’s last visit or 
date of last follow-up contact, whichever is later. 
8.2. Ethics and Protection of Subject Confidentiality 
8.2.1. 
Independent Ethics Committee / Institutional Review Board (IRB) / Competent 
Authorities (CA) 
The trial will be conducted under the auspices of an Independent Ethics Committee (IEC) or 
Institutional Review Board (IRB) as required by the local regulations, ICH GCP and in accordance 
with ethical principles.  The Investigator will ensure the IEC/IRB is appropriately constituted 
according to regulatory requirements and ICH GCP.  Prior to the initiation of the trial, the 
Investigator will ensure the protocol.  Informed consent form, investigator Brochure, Investigators 
qualifications, any advertisement and if applicable, any other subject related documents are 
provided to the IEC/IRB for review and approval.  Before initiating the trial, the Investigator must 
receive written and dated full approval from the IEC/IRB responsible for the trial.  The Sponsor 
may not provide IMP or authorize the initiation of the trial activities until this approval is received. 
During the course of the trial, the Investigator will ensure any amendments to the protocol, revised 
consent forms, updates to the Investigator Brochures, suspected unexpected serious adverse 
reactions (SUSARs) are provided to the IEC/IRB for their review and approval.  The Investigator 
will also promptly notify the IEC/IRB of any unanticipated problems involving risks to human 
subject or others, and any protocol deviations, to eliminate the immediate hazards to subjects.  
The Investigator will not make any change in the trial or trial conduct without the IEC/IRB approval 
except where necessary to eliminate the apparent immediate hazards to subjects.  In the event 
this occurs, the IEC/IRB and Xenetic must be notified of the changes as soon as possible.  
The Investigator is responsible for submitting period progress reports as required to the IEC/IRB 
but not less than once per year.  At the end of the study, the Investigator must provide a final 
report and notify the IEC/IRB of the study completion.  
8.2.2. 
Ethical Conduct of the Study 
This protocol will be conducted according the US code of Federal Regulations, ICH E6 GCP, and 
ethical principles that have their origins in the Declaration of Helsinki. 
8.2.3. 
Informed Consent of Subjects 
Subject written informed consent will be obtained in accordance with local regulations, ICH GCP 
requirements and ethical principles that have their origin in the Declaration of Helsinki.  Prior to 
obtaining consent, information should be provided by the Investigator or designee in the 
language and level understandable to the subject.  The purpose, procedures, anticipated 
benefits, and potential hazards of the study should be included in the consent discussion and the 

 
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subject should be allowed ample time to ask questions.  Prior to any study procedure, the 
Informed Consent Form must be signed and personally dated by both the subject (or subject’s 
legal representative if applicable) and the person obtaining the consent. The person obtaining 
consent must be the Investigator or his/her designee who is also medically qualified. The subject 
will be provided a copy of the signed and dated consent form.  The original signed and dated 
consent form must be retained in the Investigator’s files.  The consent form should be updated 
for any new information that is relevant to the subject.  The subject should sign the revised 
consent form. 
8.2.4. 
Subject Confidentiality 
It is the Investigator’s responsibility to inform the subject General Practitioner/Primary Care 
Physician (where applicable) by letter that the subject is taking part in the study provided the 
subject agrees to this, and information to this effect is included in the Informed Consent form.  A 
copy of the letter should be filed in the Investigator Site File. 
The investigators will make every effort to keep samples and data confidential at all times. 
However, absolute confidentiality cannot be guaranteed.  There is a slight risk of breach of 
confidentiality, which could be embarrassing or stigmatizing. 
8.2.5. 
Financial Disclosure of Investigators 
According to US regulations 21 CFR Part 54, the Sponsor will obtain a financial disclosure form 
from the Investigator(s) and sub-Investigator(s) to whom the Investigator delegates significant 
study-related responsibilities (i.e., individuals listed in Form FDA 1572). 
8.3. Administrative Matters 
8.3.1. 
Arrangement for Use of Information and Publication of the Clinical Study 
Information concerning the study, patent applications, processes, scientific data or other 
pertinent information is confidential and remains the property of the Sponsor. The Investigator 
may use this information for the purposes of the study only. 
It is understood by the Investigator that the Sponsor will use information developed in this clinical 
study in connection with the development of the IMP and, therefore, may disclose it as required 
to other clinical Investigators and to Regulatory Authorities. In order to allow the use of the 
information derived from this clinical study, the Investigator understands that he/she has an 
obligation to provide complete test results and all data developed during this study to the 
Sponsor. 
Verbal or written discussion of results prior to study completion and full reporting should only be 
undertaken with written consent from the Sponsor. 
The Sponsor intends to publish the results of the study as a whole once all subjects have 
completed the study and the results have been analyzed. The Investigator may not publish the 
results of their cohort of subjects until the fully study has been accepted for publication. The 
Investigator may not submit for publication or present the results of this study without allowing 
the Sponsor 30 days in which to review and comment on the pre-publication manuscript or 

 
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content. The Investigator may not submit the results of the study for publication with the prior, 
written consent of the Sponsor. 
8.3.2. 
Regulatory Authority Approval 
The Sponsor is responsible for all regulatory aspects of the trial with regard to regulatory 
submissions. 
8.3.3. 
Protocol Amendment and/or Revision 
Any changes to the study which arise after approval of the protocol must be documented as 
protocol amendments/substantial amendments and/or administrative changes/non-substantial 
amendments.  Depending on the nature of the amendment, either IEC/IRB approval or notification 
is required.  The changes will become effective only after the approval of the Sponsor, the 
Investigator, the regulatory authority, and the IEC/IRB (if applicable). 
Amendments to this protocol must be agreed upon in writing between the Investigator and the 
Sponsor.  Written verification of IEC/IRB approval will be obtained before any amendment is 
implemented which affects subject safety or the evaluation of safety, and/or efficacy. Modifications 
to the protocol that are administrative in nature do not require IEC/IRB approval, but will be 
submitted to the IEC/IRB for their information. 
If there are changes to the Informed Consent, written verification of IEC/IRB approval must be 
forwarded to the Sponsor.  An approved copy of the new Informed Consent must also be 
forwarded to the Sponsor. 
8.3.4. 
Study Documentation and Storage 
The Investigator must retain a comprehensive and centralized filing system of all study-related 
documentation that is suitable for inspection by the Sponsor and representatives of appropriate 
Regulatory Authorities. 
The Investigator must retain essential documents until notified by the Sponsor, and at least for 
five years after study completion, as per Directive 2005/28/EC Article 17. Subject files and other 
source data (including copies of protocols, eCRFs, original reports of test results, IMP dispensing 
logs, correspondence, records of informed consent, and other documents pertaining to the 
conduct of the study) must be kept for the maximum period of time permitted by the institution. 
Documents should be stored in such a way that they can be accessed/data retrieved at a later 
date. Consideration should be given to security and environmental risks. 
No study document will be destroyed without prior written agreement between the Sponsor and 
the Investigator. Should the Investigator wish to assign the study records to another party or 
move them to another location, written agreement must be obtained from the Sponsor. 
 
8.3.5. 
Signatory Investigator for Clinical Study Report 
ICH E3 guidelines recommend and European Agency for the Evaluation of Medicinal Products 
(EMEA) Directive 2001/83/EC requires that a final study report which forms part of a marketing 
authorization application be signed by the representative for the coordinating Investigator(s) or the 
(principal) Investigator(s).  The representative for the principal Investigator will have the 

 
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responsibility to review the final study results to confirm to the best of his/her knowledge that it 
accurately describes the conduct and results of the study. 
9. 
QUALITY ASSURANCE 
Quality control (QC) will be performed according to Sponsor or CRO internal procedures.  The study will be 
audited by a quality assurance (QA) representative of the Sponsor or authorized personnel contracted to 
Sponsor.  All necessary data and documents will be made available for inspection. 
10. STUDY ORGANIZATION 
10.1. Data and Safety Monitoring Board  
A Data and Safety Monitoring Board (DSMB) will be used to evaluate safety as needed during the trial 
and to review results of interim efficacy and safety analyses.  The DSMB will consist of at least 2 
clinicians (who are not Investigators for this trial) and 1 biostatistician with expertise in oncology trials.  
The DSMB will make recommendations to the Sponsor regarding the conduct of the study, including 
possible early discontinuation of the study for excessive toxicity or extreme efficacy.  A separate DSMB 
Charter document will specify the procedures governing the conduct of the DSMB.  Qualified 
individuals not affiliated with the Sponsor, including a statistician, will be responsible for preparing 
reports for the DSMB. 

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11.
REFERENCES
1. Colombo et al., 2011; lataniotis and Catiglione, 2010.
2. Thigpen JT, Brady MF, Alvarez RD, et al. Oral medroxyprogesterone acetate in the treatment of advanced
or recurrent endometrial carcinoma: a dose-response study by the Gynecologic Oncology Group. J Clin 
Oncol. 1999;17(6):1736-1744. 
3. Miyake T, Ueda Y, Egawa-Takata T, et al. Recurrent endometrial carcinoma: prognosis for patients with
recurrence within 6 to 12 months is worse relative to those relapsing at 12 months or later. Am J Obstet 
Gynecol. 2011;204(6):535.e1-e5. doi:10.1016/j.ajog.2011.02.034. 
4. Lentz SS, Brady MF, Major FJ, Reid GC, Soper JT. High-dose megestrol acetate in advanced or recurrent
endometrial carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol. 1996;14(2):357-361. 
5. Pandya KJ, Yeap BY, Weiner LM, et al. Megestrol and tamoxifen in patients with advanced endometrial
cancer: an Eastern Cooperative Oncology Group Study (E4882). Am J Clin Oncol. 2001;24(1):43-46. 
6. Taylor JL, Schoenherr CK, Grossberg SE. High-yield interferon induction by 10-carboxymethyl-9-
acridanone in mice and hamsters. Antimicrob Agents Chemother. 1980;18(1):20-26. 
7. Kramer MJ, Cleeland R, Grunberg E. Antiviral activity of 10-carboxymethyl-9-acridanone. Antimicrob
Agents Chemother. 1976;9(2):233-238. 
8. Surkov KG, Tsyrlina EV, Konstantinova MM, Bersteĭn LM. [Neovir, an interferon inductor, modifies
expression of steroid hormone receptors in hormone-dependent tissues and restores sensitivity to tamoxifen 
in patients with inoperable breast cancer]. Vopr Onkol. 1996;42(6):28-32. 
9. Megestrol Acetate Tablets, USP, Rx only, PAR PHARMACEUTICAL, Chestnut Ridge, NY 10977
Revised: 04/16. 
10. Xylocaine (lidocaine HCl Injection, USP), Rx only, APP Pharmaceuticals, LLC, Schaumburg, IL 60173,
451175A, Revised: Feb 2010.  Clinical sites are to provide the 2% lidocaine HCL so manufacturer may vary. 
Package insert information from the manufacturer APP Pharmaceuticals is provided for reference. 
11. Whitney CW, Brunetto VL, Zaino RJ, et al. Phase 2 study of medroxyprogesterone acetate plus
tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 
2004;92(1):4-9. 
12. Yang S, Jia Y, Liu X, et al. Systematic dissection of the mechanisms underlying progesterone receptor
downregulation in endometrial cancer. Oncotarget. 2014;5(20):9783-9797. 
13. Tavassoli, FA., Devilee, P. (Eds)  World Health Organization Classification of Tumours , International
Agency for Research on Cancer (IARC) Pathology and Genetics of Tumours of the Breast and Female 
Genital Organs 
14.
Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann In-
tern Med. 2009;150(9):604-612. 

New response evaluation criteria in solid tumours:
Revised RECIST guideline (version 1.1)
E.A. Eisenhauera,*, P. Therasseb, J. Bogaertsc, L.H. Schwartzd, D. Sargente, R. Fordf,
J. Danceyg, S. Arbuckh, S. Gwytheri, M. Mooneyg, L. Rubinsteing, L. Shankarg, L. Doddg,
R. Kaplanj, D. Lacombec, J. Verweijk
aNational Cancer Institute of Canada – Clinical Trials Group, 10 Stuart Street, Queen’s University, Kingston, ON, Canada
bGlaxoSmithKline Biologicals, Rixensart, Belgium
cEuropean Organisation for Research and Treatment of Cancer, Data Centre, Brussels, Belgium
dMemorial Sloan Kettering Cancer Center, New York, NY, USA
eMayo Clinic, Rochester, MN, USA
fRadPharm, Princeton, NJ, USA
gDivision of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA
hSchering-Plough, Kenilworth, NJ, USA
iEast Surrey Hospital, Redhill, Surrey, UK
jNational Cancer Research Network, Leeds, UK
kErasmus University Medical Center, Rotterdam, The Netherlands
A R T I C L E
I N F O
Article history:
Received 17 October 2008
Accepted 29 October 2008
Keywords:
Response criteria
Solid tumours
Guidelines
A B S T R A C T
Background: Assessment of the change in tumour burden is an important feature of the
clinical evaluation of cancer therapeutics: both tumour shrinkage (objective response)
and disease progression are useful endpoints in clinical trials. Since RECIST was published
in 2000, many investigators, cooperative groups, industry and government authorities have
adopted these criteria in the assessment of treatment outcomes. However, a number of
questions and issues have arisen which have led to the development of a revised RECIST
guideline (version 1.1). Evidence for changes, summarised in separate papers in this special
issue, has come from assessment of a large data warehouse (>6500 patients), simulation
studies and literature reviews.
Highlights of revised RECIST 1.1: Major changes include: Number of lesions to be assessed: based
on evidence from numerous trial databases merged into a data warehouse for analysis pur-
poses, the number of lesions required to assess tumour burden for response determination
has been reduced from a maximum of 10 to a maximum of ﬁve total (and from ﬁve to two
per organ, maximum). Assessment of pathological lymph nodes is now incorporated: nodes
with a short axis of P15 mm are considered measurable and assessable as target lesions.
The short axis measurement should be included in the sum of lesions in calculation of
tumour response. Nodes that shrink to <10 mm short axis are considered normal. Conﬁrma-
tion of response is required for trials with response primary endpoint but is no longer
required in randomised studies since the control arm serves as appropriate means of inter-
pretation of data. Disease progression is clariﬁed in several aspects: in addition to the previ-
ous deﬁnition of progression in target disease of 20% increase in sum, a 5 mm absolute
increase is now required as well to guard against over calling PD when the total sum is very
0959-8049/$ - see front matter  2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.ejca.2008.10.026
* Corresponding author: Tel.: +1 613 533 6430; fax: +1 613 533 2411.
E-mail address: eeisenhauer@ctg.queensu.ca (E.A. Eisenhauer).
E U R O P E A N J O U R N A L O F C A N C E R 4 5 ( 2 0 0 9 ) 2 2 8 –2 4 7
available at www.sciencedirect.com
journal homepage: www.ejconline.com
APPENDIX 1
Xenetic Biosciences Protocol No. VX-EC-2-02

small. Furthermore, there is guidance offered on what constitutes ‘unequivocal progres-
sion’ of non-measurable/non-target disease, a source of confusion in the original RECIST
guideline. Finally, a section on detection of new lesions, including the interpretation of
FDG-PET scan assessment is included. Imaging guidance: the revised RECIST includes a
new imaging appendix with updated recommendations on the optimal anatomical assess-
ment of lesions.
Future work: A key question considered by the RECIST Working Group in developing RECIST
1.1 was whether it was appropriate to move from anatomic unidimensional assessment of
tumour burden to either volumetric anatomical assessment or to functional assessment
with PET or MRI. It was concluded that, at present, there is not sufﬁcient standardisation
or evidence to abandon anatomical assessment of tumour burden. The only exception to
this is in the use of FDG-PET imaging as an adjunct to determination of progression. As
is detailed in the ﬁnal paper in this special issue, the use of these promising newer
approaches requires appropriate clinical validation studies.
 2008 Elsevier Ltd. All rights reserved.
1.
Background
1.1.
History of RECIST criteria
Assessment of the change in tumour burden is an important
feature of the clinical evaluation of cancer therapeutics. Both
tumour shrinkage (objective response) and time to the devel-
opment of disease progression are important endpoints in
cancer clinical trials. The use of tumour regression as the
endpoint for phase II trials screening new agents for evi-
dence of anti-tumour effect is supported by years of evi-
dence suggesting that, for many solid tumours, agents
which produce tumour shrinkage in a proportion of patients
have a reasonable (albeit imperfect) chance of subsequently
demonstrating an improvement in overall survival or other
time to event measures in randomised phase III studies (re-
viewed in [1–4]). At the current time objective response car-
ries with it a body of evidence greater than for any other
biomarker supporting its utility as a measure of promising
treatment effect in phase II screening trials. Furthermore,
at both the phase II and phase III stage of drug development,
clinical trials in advanced disease settings are increasingly
utilising time to progression (or progression-free survival)
as an endpoint upon which efﬁcacy conclusions are drawn,
which is also based on anatomical measurement of tumour
size.
However, both of these tumour endpoints, objective re-
sponse and time to disease progression, are useful only if
based on widely accepted and readily applied standard crite-
ria based on anatomical tumour burden. In 1981 the World
Health Organisation (WHO) ﬁrst published tumour response
criteria, mainly for use in trials where tumour response was
the primary endpoint. The WHO criteria introduced the con-
cept of an overall assessment of tumour burden by summing
the products of bidimensional lesion measurements and
determined response to therapy by evaluation of change from
baseline while on treatment.5 However, in the decades that
followed their publication, cooperative groups and pharma-
ceutical companies that used the WHO criteria often ‘modi-
ﬁed’ them to accommodate new technologies or to address
areas that were unclear in the original document. This led
to confusion in interpretation of trial results6 and in fact,
the application of varying response criteria was shown to lead
to very different conclusions about the efﬁcacy of the same
regimen.7 In response to these problems, an International
Working Party was formed in the mid 1990s to standardise
and simplify response criteria. New criteria, known as RECIST
(Response Evaluation Criteria in Solid Tumours), were pub-
lished in 2000.8 Key features of the original RECIST include
deﬁnitions of minimum size of measurable lesions, instruc-
tions on how many lesions to follow (up to 10; a maximum
ﬁve per organ site), and the use of unidimensional, rather
than bidimensional, measures for overall evaluation of tu-
mour burden. These criteria have subsequently been widely
adopted by academic institutions, cooperative groups, and
industry for trials where the primary endpoints are objective
response or progression. In addition, regulatory authorities
accept
RECIST
as
an
appropriate
guideline
for
these
assessments.
1.2.
Why update RECIST?
Since RECIST was published in 2000, many investigators have
conﬁrmed in prospective analyses the validity of substituting
unidimensional for bidimensional (and even three-dimen-
sional)-based criteria (reviewed in [9]). With rare exceptions
(e.g. mesothelioma), the use of unidimensional criteria seems
to perform well in solid tumour phase II studies.
However, a number of questions and issues have arisen
which merit answers and further clarity. Amongst these
are whether fewer than 10 lesions can be assessed without
affecting the overall assigned response for patients (or the
conclusion about activity in trials); how to apply RECIST in
randomised phase III trials where progression, not response,
is the primary endpoint particularly if not all patients have
measurable disease; whether or how to utilise newer imag-
ing technologies such as FDG-PET and MRI; how to handle
assessment of lymph nodes; whether response conﬁrmation
is truly needed; and, not least, the applicability of RECIST in
trials of targeted non-cytotoxic drugs. This revision of the
RECIST guidelines includes updates that touch on all these
points.
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1.3.
Process of RECIST 1.1 development
The RECIST Working Group, consisting of clinicians with
expertise in early drug development from academic research
organisations, government and industry, together with imag-
ing specialists and statisticians, has met regularly to set the
agenda for an update to RECIST, determine the evidence
needed to justify the various changes made, and to review
emerging evidence. A critical aspect of the revision process
was to create a database of prospectively documented solid
tumour measurement data obtained from industry and aca-
demic group trials. This database, assembled at the EORTC
Data Centre under the leadership of Jan Bogaerts and Patrick
Therasse (co-authors of this guideline), consists of >6500 pa-
tients with >18,000 target lesions and was utilised to investi-
gate the impact of a variety of questions (e.g. number of
target lesions required, the need for response conﬁrmation,
and lymph node measurement rules) on response and pro-
gression-free survival outcomes. The results of this work,
which after evaluation by the RECIST Working Group led to
most of the changes in this revised guideline, are reported
in detail in a separate paper in this special issue.10 Larry Sch-
wartz and Robert Ford (also co-authors of this guideline) also
provided key databases from which inferences have been
made that inform these revisions.11
The publication of this revised guideline is believed to be
timely since it incorporates changes to simplify, optimise
and standardise the assessment of tumour burden in clinical
trials. A summary of key changes is found in Appendix I. Be-
cause the fundamental approach to assessment remains
grounded in the anatomical, rather than functional, assess-
ment of disease, we have elected to name this version RECIST
1.1, rather than 2.0.
1.4.
What about volumetric or functional assessment?
This raises the question, frequently posed, about whether it is
‘time’ to move from anatomic unidimensional assessment of
tumour burden to either volumetric anatomical assessment
or to functional assessment (e.g. dynamic contrast enhanced
MRI or CT or (18)F-ﬂuorodeoxyglucose positron emission
tomographic (FDG-PET) techniques assessing tumour metab-
olism). As can be seen, the Working Group and particularly
those involved in imaging research, did not believe that there
is at present sufﬁcient standardisation and widespread avail-
ability to recommend adoption of these alternative assess-
ment methods. The only exception to this is in the use of
FDG-PET imaging as an adjunct to determination of progres-
sion, as described later in this guideline. As detailed in paper
in this special issue12, we believe that the use of these prom-
ising newer approaches (which could either add to or substitute
for anatomical assessment as described in RECIST) requires
appropriate and rigorous clinical validation studies. This pa-
per by Sargent et al. illustrates the type of data that will be
needed to be able to deﬁne ‘endpoints’ for these modalities
and how to determine where and when such criteria/modal-
ities can be used to improve the reliability with which truly
active new agents are identiﬁed and truly inactive new agents
are discarded in comparison to RECIST criteria in phase II
screening trials. The RECIST Working Group looks forward
to such data emerging in the next few years to allow the
appropriate changes to the next iteration of the RECIST
criteria.
2.
Purpose of this guideline
This guideline describes a standard approach to solid tumour
measurement and deﬁnitions for objective assessment of
change in tumour size for use in adult and paediatric cancer
clinical trials. It is expected these criteria will be useful in all
trials where objective response is the primary study endpoint,
as well as in trials where assessment of stable disease, tu-
mour progression or time to progression analyses are under-
taken, since all of these outcome measures are based on an
assessment of anatomical tumour burden and its change on
study. There are no assumptions in this paper about the pro-
portion of patients meeting the criteria for any of these end-
points which will signal that an agent or treatment regimen is
active: those deﬁnitions are dependent on type of cancer in
which a trial is being undertaken and the speciﬁc agent(s) un-
der study. Protocols must include appropriate statistical sec-
tions which deﬁne the efﬁcacy parameters upon which the
trial sample size and decision criteria are based. In addition
to providing deﬁnitions and criteria for assessment of tumour
response,
this
guideline
also
makes
recommendations
regarding standard reporting of the results of trials that utilise
tumour response as an endpoint.
While these guidelines may be applied in malignant brain
tumour studies, there are also separate criteria published for
response assessment in that setting.13 This guideline is not in-
tended for use for studies of malignant lymphoma since
international guidelines for response assessment in lym-
phoma are published separately.14
Finally, many oncologists in their daily clinical practice fol-
low their patients’ malignant disease by means of repeated
imaging studies and make decisions about continued therapy
on the basis of both objective and symptomatic criteria. It is
not intended that these RECIST guidelines play a role in that
decision making, except if determined appropriate by the
treating oncologist.
3.
Measurability of tumour at baseline
3.1.
Deﬁnitions
At baseline, tumour lesions/lymph nodes will be categorised
measurable or non-measurable as follows:
3.1.1.
Measurable
Tumour lesions: Must be accurately measured in at least one
dimension (longest diameter in the plane of measurement is
to be recorded) with a minimum size of:
• 10 mm by CT scan (CT scan slice thickness no greater than
5 mm; see Appendix II on imaging guidance).
• 10 mm caliper measurement by clinical exam (lesions
which cannot be accurately measured with calipers should
be recorded as non-measurable).
• 20 mm by chest X-ray.
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Malignant lymph nodes: To be considered pathologically en-
larged and measurable, a lymph node must be P15 mm in
short axis when assessed by CT scan (CT scan slice thickness
recommended to be no greater than 5 mm). At baseline and in
follow-up, only the short axis will be measured and followed
(see Schwartz et al. in this Special Issue15). See also notes be-
low on ‘Baseline documentation of target and non-target le-
sions’ for information on lymph node measurement.
3.1.2.
Non-measurable
All other lesions, including small lesions (longest diameter
<10 mm or pathological lymph nodes with P10 to <15 mm
short axis) as well as truly non-measurable lesions. Lesions
considered truly non-measurable include: leptomeningeal dis-
ease, ascites, pleural or pericardial effusion, inﬂammatory
breast disease, lymphangitic involvement of skin or lung,
abdominal masses/abdominal organomegaly identiﬁed by
physical exam that is not measurable by reproducible imaging
techniques.
3.1.3.
Special considerations regarding lesion measurability
Bone lesions, cystic lesions, and lesions previously treated
with local therapy require particular comment:
Bone lesions:.
• Bone scan, PET scan or plain ﬁlms are not considered ade-
quate imaging techniques to measure bone lesions. How-
ever,
these
techniques
can
be
used
to
conﬁrm
the
presence or disappearance of bone lesions.
• Lytic bone lesions or mixed lytic-blastic lesions, with identi-
ﬁable soft tissue components, that can be evaluated by cross
sectional imaging techniques such as CT or MRI can be con-
sidered as measurable lesions if the soft tissue component
meets the deﬁnition of measurability described above.
• Blastic bone lesions are non-measurable.
Cystic lesions:.
• Lesions that meet the criteria for radiographically deﬁned
simple cysts should not be considered as malignant lesions
(neither measurable nor non-measurable) since they are, by
deﬁnition, simple cysts.
• ‘Cystic lesions’ thought to represent cystic metastases can
be considered as measurable lesions, if they meet the deﬁ-
nition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are pre-
ferred for selection as target lesions.
Lesions with prior local treatment:.
• Tumour lesions situated in a previously irradiated area, or
in an area subjected to other loco-regional therapy, are usu-
ally not considered measurable unless there has been dem-
onstrated progression in the lesion. Study protocols should
detail the conditions under which such lesions would be
considered measurable.
3.2.
Speciﬁcations by methods of measurements
3.2.1.
Measurement of lesions
All measurements should be recorded in metric notation,
using calipers if clinically assessed. All baseline evaluations
should be performed as close as possible to the treatment
start and never more than 4 weeks before the beginning of
the treatment.
3.2.2.
Method of assessment
The same method of assessment and the same technique
should be used to characterise each identiﬁed and reported
lesion at baseline and during follow-up. Imaging based evalu-
ation should always be done rather than clinical examination
unless the lesion(s) being followed cannot be imaged but are
assessable by clinical exam.
Clinical lesions: Clinical lesions will only be considered mea-
surable when they are superﬁcial and P10 mm diameter as
assessed using calipers (e.g. skin nodules). For the case of skin
lesions, documentation by colour photography including a ru-
ler to estimate the size of the lesion is suggested. As noted
above, when lesions can be evaluated by both clinical exam
and imaging, imaging evaluation should be undertaken since
it is more objective and may also be reviewed at the end of the
study.
Chest X-ray: Chest CT is preferred over chest X-ray, particu-
larly when progression is an important endpoint, since CT is
more sensitive than X-ray, particularly in identifying new le-
sions. However, lesions on chest X-ray may be considered
measurable if they are clearly deﬁned and surrounded by aer-
ated lung. See Appendix II for more details.
CT, MRI: CT is the best currently available and reproducible
method to measure lesions selected for response assessment.
This guideline has deﬁned measurability of lesions on CT
scan based on the assumption that CT slice thickness is
5 mm or less. As is described in Appendix II, when CT scans
have slice thickness greater than 5 mm, the minimum size
for a measurable lesion should be twice the slice thickness.
MRI is also acceptable in certain situations (e.g. for body
scans). More details concerning the use of both CT and MRI
for assessment of objective tumour response evaluation are
provided in Appendix II.
Ultrasound: Ultrasound is not useful in assessment of lesion
size and should not be used as a method of measurement.
Ultrasound examinations cannot be reproduced in their en-
tirety for independent review at a later date and, because
they are operator dependent, it cannot be guaranteed that
the same technique and measurements will be taken from
one assessment to the next (described in greater detail in
Appendix II). If new lesions are identiﬁed by ultrasound in
the course of the study, conﬁrmation by CT or MRI is ad-
vised. If there is concern about radiation exposure at CT,
MRI may be used instead of CT in selected instances.
Endoscopy, laparoscopy: The utilisation of these techniques for
objective tumour evaluation is not advised. However, they
can be useful to conﬁrm complete pathological response
when biopsies are obtained or to determine relapse in trials
where recurrence following complete response or surgical
resection is an endpoint.
Tumour markers: Tumour markers alone cannot be used to as-
sess objective tumour response. If markers are initially above
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the upper normal limit, however, they must normalise for a
patient to be considered in complete response. Because
tumour markers are disease speciﬁc, instructions for their
measurement should be incorporated into protocols on a
disease speciﬁc basis. Speciﬁc guidelines for both CA-125
response (in recurrent ovarian cancer) and PSA response (in
recurrent prostate cancer), have been published.16–18 In addi-
tion, the Gynecologic Cancer Intergroup has developed CA125
progression criteria which are to be integrated with objective
tumour assessment for use in ﬁrst-line trials in ovarian
cancer.19
Cytology, histology: These techniques can be used to differenti-
ate between PR and CR in rare cases if required by protocol
(for example, residual lesions in tumour types such as germ
cell tumours, where known residual benign tumours can re-
main). When effusions are known to be a potential adverse
effect of treatment (e.g. with certain taxane compounds or
angiogenesis inhibitors), the cytological conﬁrmation of the
neoplastic origin of any effusion that appears or worsens dur-
ing treatment can be considered if the measurable tumour
has met criteria for response or stable disease in order to dif-
ferentiate between response (or stable disease) and progres-
sive disease.
4.
Tumour response evaluation
4.1.
Assessment of overall tumour burden and
measurable disease
To assess objective response or future progression, it is nec-
essary to estimate the overall tumour burden at baseline and
use this as a comparator for subsequent measurements.
Only patients with measurable disease at baseline should
be included in protocols where objective tumour response
is the primary endpoint. Measurable disease is deﬁned by
the presence of at least one measurable lesion (as detailed
above in Section 3). In studies where the primary endpoint
is tumour progression (either time to progression or propor-
tion with progression at a ﬁxed date), the protocol must
specify if entry is restricted to those with measurable disease
or whether patients having non-measurable disease only are
also eligible.
4.2.
Baseline documentation of ‘target’ and ‘non-target’
lesions
When more than one measurable lesion is present at baseline
all lesions up to a maximum of ﬁve lesions total (and a max-
imum of two lesions per organ) representative of all involved
organs should be identiﬁed as target lesions and will be re-
corded and measured at baseline (this means in instances
where patients have only one or two organ sites involved a
maximum of two and four lesions respectively will be re-
corded). For evidence to support the selection of only ﬁve tar-
get lesions, see analyses on a large prospective database in
the article by Bogaerts et al.10.
Target lesions should be selected on the basis of their size
(lesions with the longest diameter), be representative of all in-
volved organs, but in addition should be those that lend
themselves to reproducible repeated measurements. It may be
the case that, on occasion, the largest lesion does not lend it-
self to reproducible measurement in which circumstance the
next largest lesion which can be measured reproducibly
should be selected. To illustrate this point see the example
in Fig. 3 of Appendix II.
Lymph nodes merit special mention since they are normal
anatomical structures which may be visible by imaging even
if not involved by tumour. As noted in Section 3, pathological
nodes which are deﬁned as measurable and may be identi-
ﬁed as target lesions must meet the criterion of a short axis
of P15 mm by CT scan. Only the short axis of these nodes
will contribute to the baseline sum. The short axis of the
node is the diameter normally used by radiologists to judge
if a node is involved by solid tumour. Nodal size is normally
reported as two dimensions in the plane in which the image
is obtained (for CT scan this is almost always the axial plane;
for MRI the plane of acquisition may be axial, saggital or
coronal). The smaller of these measures is the short axis.
For example, an abdominal node which is reported as being
20 mm · 30 mm has a short axis of 20 mm and qualiﬁes as a
malignant, measurable node. In this example, 20 mm should
be recorded as the node measurement (See also the example
in Fig. 4 in Appendix II). All other pathological nodes (those
with short axis P10 mm but <15 mm) should be considered
non-target lesions. Nodes that have a short axis <10 mm
are considered non-pathological and should not be recorded
or followed.
A sum of the diameters (longest for non-nodal lesions, short
axis for nodal lesions) for all target lesions will be calculated
and reported as the baseline sum diameters. If lymph nodes
are to be included in the sum, then as noted above, only the
short axis is added into the sum. The baseline sum diameters
will be used as reference to further characterise any objective
tumour regression in the measurable dimension of the
disease.
All other lesions (or sites of disease) including pathological
lymph nodes should be identiﬁed as non-target lesions and
should also be recorded at baseline. Measurements are not re-
quired and these lesions should be followed as ‘present’, ‘ab-
sent’, or in rare cases ‘unequivocal progression’ (more details
to follow). In addition, it is possible to record multiple non-
target lesions involving the same organ as a single item on
the case record form (e.g. ‘multiple enlarged pelvic lymph
nodes’ or ‘multiple liver metastases’).
4.3.
Response criteria
This section provides the deﬁnitions of the criteria used to
determine objective tumour response for target lesions.
4.3.1.
Evaluation of target lesions
Complete Response (CR): Disappearance of all target lesions.
Any pathological lymph nodes (whether target or
non-target) must have reduction in short axis to
<10 mm.
Partial Response (PR): At least a 30% decrease in the sum of
diameters of target lesions, taking as reference the
baseline sum diameters.
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Progressive Disease (PD): At least a 20% increase in the sum
of diameters of target lesions, taking as reference
the smallest sum on study (this includes the baseline
sum if that is the smallest on study). In addition to
the relative increase of 20%, the sum must also dem-
onstrate an absolute increase of at least 5 mm. (Note:
the appearance of one or more new lesions is also
considered progression).
Stable Disease (SD): Neither sufﬁcient shrinkage to qualify for
PR nor sufﬁcient increase to qualify for PD, taking as
reference the smallest sum diameters while on study.
4.3.2.
Special notes on the assessment of target lesions
Lymph nodes. Lymph nodes identiﬁed as target lesions should
always have the actual short axis measurement recorded (mea-
sured in the same anatomical plane as the baseline examina-
tion), even if the nodes regress to below 10 mm on study. This
means that when lymph nodes are included as target lesions,
the ‘sum’ of lesions may not be zero even if complete response
criteria are met, since a normal lymph node is deﬁned as having
a short axis of <10 mm. Case report forms or other data collec-
tion methods may therefore be designed to have target nodal le-
sions recorded in a separate section where, in order to qualify
for CR, each node must achieve a short axis <10 mm. For PR,
SD and PD, the actual short axis measurement of the nodes is
to be included in the sum of target lesions.
Target lesions that become ‘too small to measure’. While on
study, all lesions (nodal and non-nodal) recorded at baseline
should have their actual measurements recorded at each sub-
sequent evaluation, even when very small (e.g. 2 mm). How-
ever, sometimes lesions or lymph nodes which are recorded
as target lesions at baseline become so faint on CT scan that
the radiologist may not feel comfortable assigning an exact
measure and may report them as being ‘too small to measure’.
When this occurs it is important that a value be recorded on
the case report form. If it is the opinion of the radiologist that
the lesion has likely disappeared, the measurement should be
recorded as 0 mm. If the lesion is believed to be present and is
faintly seen but too small to measure, a default value of 5 mm
should be assigned (Note: It is less likely that this rule will be
used for lymph nodes since they usually have a deﬁnable size
when normal and are frequently surrounded by fat such as in
the retroperitoneum; however, if a lymph node is believed to
be present and is faintly seen but too small to measure, a de-
fault value of 5 mm should be assigned in this circumstance as
well). This default value is derived from the 5 mm CT slice
thickness (but should not be changed with varying CT slice
thickness). The measurement of these lesions is potentially
non-reproducible, therefore providing this default value will
prevent false responses or progressions based upon measure-
ment error. To reiterate, however, if the radiologist is able to
provide an actual measure, that should be recorded, even if
it is below 5 mm.
Lesions that split or coalesce on treatment. As noted in Appen-
dix II, when non-nodal lesions ‘fragment’, the longest diame-
ters of the fragmented portions should be added together to
calculate the target lesion sum. Similarly, as lesions coalesce,
a plane between them may be maintained that would aid in
obtaining maximal diameter measurements of each individ-
ual lesion. If the lesions have truly coalesced such that they
are no longer separable, the vector of the longest diameter
in this instance should be the maximal longest diameter for
the ‘coalesced lesion’.
4.3.3.
Evaluation of non-target lesions
Thissection provides the deﬁnitionsofthe criteriausedtodeter-
mine the tumour response for the group of non-target lesions.
While some non-target lesions may actually be measurable,
they need not be measured and instead should be assessed only
qualitatively at the time points speciﬁed in the protocol.
Complete Response (CR): Disappearance of all non-target le-
sions and normalisation of tumour marker level. All
lymph nodes must be non-pathological in size
(<10 mm short axis).
Non-CR/Non-PD: Persistence of one or more non-target le-
sion(s) and/or maintenance of tumour marker level
above the normal limits.
Progressive Disease (PD): Unequivocal progression (see com-
ments below) of existing non-target lesions. (Note:
the appearance of one or more new lesions is also
considered progression).
4.3.4.
Special notes on assessment of progression of non-
target disease
The concept of progression of non-target disease requires
additional explanation as follows:
When the patient also has measurable disease. In this setting,
to achieve ‘unequivocal progression’ on the basis of the
non-target disease, there must be an overall level of substan-
tial worsening in non-target disease such that, even in pres-
ence of SD or PR in target disease, the overall tumour
burden has increased sufﬁciently to merit discontinuation
of therapy (see examples in Appendix II and further details
below). A modest ‘increase’ in the size of one or more non-tar-
get lesions is usually not sufﬁcient to quality for unequivocal
progression status. The designation of overall progression so-
lely on the basis of change in non-target disease in the face of
SD or PR of target disease will therefore be extremely rare.
When the patient has only non-measurable disease.This circum-
stance arises in some phase III trials when it is not a criterion of
study entry to have measurable disease. The same general con-
cepts apply here as noted above, however, in this instance there
is no measurable disease assessment to factor into the inter-
pretation of an increase in non-measurable disease burden.
Because worsening in non-target disease cannot be easily
quantiﬁed (by deﬁnition: if all lesions are truly non-measur-
able) a useful test that can be applied when assessing patients
for unequivocal progression is to consider if the increase in
overall disease burden based on the change in non-measurable
disease is comparable in magnitude to the increase that would
berequiredtodeclarePDformeasurabledisease: i.e.anincrease
in tumour burden representing an additional 73% increase in
‘volume’ (which is equivalent to a 20% increase diameter in a
measurable lesion). Examples include an increase in a pleural
effusion from ‘trace’ to ‘large’, an increase in lymphangitic
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disease from localised to widespread, or may be described in
protocols as ‘sufﬁcient to require a change in therapy’. Some
illustrative examples are shown in Figs. 5 and 6 in Appendix II.
If ‘unequivocal progression’ is seen, the patient should be con-
sidered to have had overall PD at that point. While it would be
ideal to have objective criteria to apply to non-measurable dis-
ease, the very nature of that disease makes it impossible to do
so, therefore the increase must be substantial.
4.3.5.
New lesions
The appearance of new malignant lesions denotes disease
progression; therefore, some comments on detection of new
lesions are important. There are no speciﬁc criteria for the
identiﬁcation of new radiographic lesions; however, the ﬁnd-
ing of a new lesion should be unequivocal: i.e. not attributable
to differences in scanning technique, change in imaging
modality or ﬁndings thought to represent something other
than tumour (for example, some ‘new’ bone lesions may be
simply healing or ﬂare of pre-existing lesions). This is partic-
ularly important when the patient’s baseline lesions show
partial or complete response. For example, necrosis of a liver
lesion may be reported on a CT scan report as a ‘new’ cystic
lesion, which it is not.
A lesion identiﬁed on a follow-up study in an anatomical
location that was not scanned at baseline is considered a new
lesion andwill indicate diseaseprogression. An example of this
is the patient who has visceral disease at baseline and while on
study has a CTor MRI brain ordered which reveals metastases.
The patient’s brain metastases are considered to be evidence of
PD even if he/she did not have brain imaging at baseline.
If a new lesion is equivocal, for example because of its
small size, continued therapy and follow-up evaluation will
clarify if it represents truly new disease. If repeat scans con-
ﬁrm there is deﬁnitely a new lesion, then progression should
be declared using the date of the initial scan.
While FDG-PET response assessments need additional
study, it is sometimes reasonable to incorporate the use of
FDG-PET scanning to complement CT scanning in assessment
of progression (particularly possible ‘new’ disease). New le-
sions on the basis of FDG-PET imaging can be identiﬁed
according to the following algorithm:
a. Negative FDG-PET at baseline, with a positivel FDG-PET
at follow-up is a sign of PD based on a new lesion.
b. No FDG-PET at baseline and a positive FDG-PET at fol-
low-up:
If the positive FDG-PET at follow-up corresponds to a
new site of disease conﬁrmed by CT, this is PD.
If the positive FDG-PET at follow-up is not conﬁrmed as
a new site of disease on CT, additional follow-up CT
scans are needed to determine if there is truly progres-
sion occurring at that site (if so, the date of PD will be
the date of the initial abnormal FDG-PET scan).
If the positive FDG-PET at follow-up corresponds to a
pre-existing site of disease on CT that is not progress-
ing on the basis of the anatomic images, this is not PD.
4.4.
Evaluation of best overall response
The best overall response is the best response recorded from
the start of the study treatment until the end of treatment
taking into account any requirement for conﬁrmation. On oc-
casion a response may not be documented until after the end
of therapy so protocols should be clear if post-treatment
assessments are to be considered in determination of best
overall response. Protocols must specify how any new therapy
introduced before progression will affect best response desig-
nation. The patient’s best overall response assignment will
depend on the ﬁndings of both target and non-target disease
and will also take into consideration the appearance of new
lesions. Furthermore, depending on the nature of the study
and the protocol requirements, it may also require conﬁrma-
tory measurement (see Section 4.6). Speciﬁcally, in non-ran-
domised trials where response is the primary endpoint,
conﬁrmation of PR or CR is needed to deem either one the
‘best overall response’. This is described further below.
4.4.1.
Time point response
It is assumed that at each protocol speciﬁed time point, a re-
sponse assessment occurs. Table 1 on the next page provides
a summary of the overall response status calculation at each
time point for patients who have measurable disease at
baseline.
When patients have non-measurable (therefore non-tar-
get) disease only, Table 2 is to be used.
4.4.2.
Missing assessments and inevaluable designation
When no imaging/measurement is done at all at a particular
time point, the patient is not evaluable (NE) at that time point.
If only a subset of lesion measurements are made at an
assessment, usually the case is also considered NE at that
time point, unless a convincing argument can be made that
the contribution of the individual missing lesion(s) would
not change the assigned time point response. This would be
most likely to happen in the case of PD. For example, if a pa-
tient had a baseline sum of 50 mm with three measured le-
sions and at follow-up only two lesions were assessed, but
those gave a sum of 80 mm, the patient will have achieved
PD status, regardless of the contribution of the missing lesion.
4.4.3.
Best overall response: all time points
The best overall response is determined once all the data for the
patient is known.
Best response determination in trials where conﬁrmation of com-
plete or partial response IS NOT required: Best response in these
trials is deﬁned as the best response across all time points (for
example, a patient who has SD at ﬁrst assessment, PR at sec-
ond assessment, and PD on last assessment has a best overall
response of PR). When SD is believed to be best response, it
must also meet the protocol speciﬁed minimum time from
baseline. If the minimum time is not met when SD is other-
wise the best time point response, the patient’s best response
depends on the subsequent assessments. For example, a pa-
tient who has SD at ﬁrst assessment, PD at second and does
not meet minimum duration for SD, will have a best response
of PD. The same patient lost to follow-up after the ﬁrst SD
assessment would be considered inevaluable.
l A ‘positive’ FDG-PET scan lesion means one which is FDG avid
with an uptake greater than twice that of the surrounding tissue
on the attenuation corrected image.
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Best response determination in trials where conﬁrmation of com-
plete or partial response IS required: Complete or partial re-
sponses may be claimed only if the criteria for each are met
at a subsequent time point as speciﬁed in the protocol (gener-
ally 4 weeks later). In this circumstance, the best overall re-
sponse can be interpreted as in Table 3.
4.4.4.
Special notes on response assessment
When nodal disease is included in the sum of target lesions
and the nodes decrease to ‘normal’ size (<10 mm), they may
still have a measurement reported on scans. This measure-
ment should be recorded even though the nodes are normal
in order not to overstate progression should it be based on
increase in size of the nodes. As noted earlier, this means that
patients with CR may not have a total sum of ‘zero’ on the
case report form (CRF).
In trials where conﬁrmation of response is required, re-
peated ‘NE’ time point assessments may complicate best re-
sponse determination. The analysis plan for the trial must
address how missing data/assessments will be addressed in
determination of response and progression. For example, in
most trials it is reasonable to consider a patient with time
point responses of PR-NE-PR as a conﬁrmed response.
Patients with a global deterioration of health status requir-
ing discontinuation of treatment without objective evidence
of disease progression at that time should be reported as
‘symptomatic deterioration’. Every effort should be made to
document objective progression even after discontinuation
of treatment. Symptomatic deterioration is not a descriptor
of an objective response: it is a reason for stopping study ther-
apy. The objective response status of such patients is to be
determined by evaluation of target and non-target disease
as shown in Tables 1–3.
Conditions that deﬁne ‘early progression, early death and
inevaluability’ are study speciﬁc and should be clearly de-
scribed in each protocol (depending on treatment duration,
treatment periodicity).
In some circumstances it may be difﬁcult to distinguish
residual disease from normal tissue. When the evaluation of
complete response depends upon this determination, it is
recommended that the residual lesion be investigated (ﬁne
Table 3 – Best overall response when conﬁrmation of CR and PR required.
Overall response
Overall response
BEST overall response
First time point
Subsequent time point
CR
CR
CR
CR
PR
SD, PD or PRa
CR
SD
SD provided minimum criteria for SD duration met, otherwise, PD
CR
PD
SD provided minimum criteria for SD duration met, otherwise, PD
CR
NE
SD provided minimum criteria for SD duration met, otherwise NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD duration met, otherwise, PD
PR
NE
SD provided minimum criteria for SD duration met, otherwise NE
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = inevaluable.
a If a CR is truly met at ﬁrst time point, then any disease seen at a subsequent time point, even disease meeting PR criteria relative to baseline,
makes the disease PD at that point (since disease must have reappeared after CR). Best response would depend on whether minimum duration
for SD was met. However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were likely still present and in fact the
patient had PR, not CR at the ﬁrst time point. Under these circumstances, the original CR should be changed to PR and the best response is PR.
Table 1 – Time point response: patients with target (+/–
non-target) disease.
Target lesions
Non-target lesions
New
lesions
Overall
response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or
not all evaluated
No
PR
SD
Non-PD or
not all evaluated
No
SD
Not all
evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease,
PD = progressive disease, and NE = inevaluable.
Table 2 – Time point response: patients with non-target
disease only.
Non-target lesions
New lesions
Overall response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete
response,
PD = progressive
disease,
and
NE = inevaluable.
a ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target
disease since SD is increasingly used as endpoint for assessment
of efﬁcacy in some trials so to assign this category when no
lesions can be measured is not advised.
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needle aspirate/biopsy) before assigning a status of complete
response. FDG-PET may be used to upgrade a response to a CR
in a manner similar to a biopsy in cases where a residual
radiographic abnormality is thought to represent ﬁbrosis or
scarring. The use of FDG-PET in this circumstance should be
prospectively described in the protocol and supported by dis-
ease speciﬁc medical literature for the indication. However, it
must be acknowledged that both approaches may lead to
false positive CR due to limitations of FDG-PETand biopsy res-
olution/sensitivity.
For equivocal ﬁndings of progression (e.g. very small and
uncertain new lesions; cystic changes or necrosis in existing
lesions), treatment may continue until the next scheduled
assessment. If at the next scheduled assessment, progression
is conﬁrmed, the date of progression should be the earlier
date when progression was suspected.
4.5.
Frequency of tumour re-evaluation
Frequency
of
tumour
re-evaluation
while
on
treatment
should be protocol speciﬁc and adapted to the type and sche-
dule of treatment. However, in the context of phase II studies
where the beneﬁcial effect of therapy is not known, follow-up
every 6–8 weeks (timed to coincide with the end of a cycle) is
reasonable. Smaller or greater time intervals than these could
be justiﬁed in speciﬁc regimens or circumstances. The proto-
col should specify which organ sites are to be evaluated at
baseline (usually those most likely to be involved with meta-
static disease for the tumour type under study) and how often
evaluations are repeated. Normally, all target and non-target
sites are evaluated at each assessment. In selected circum-
stances certain non-target organs may be evaluated less fre-
quently. For example, bone scans may need to be repeated
only when complete response is identiﬁed in target disease
or when progression in bone is suspected.
After the end of the treatment, the need for repetitive tu-
mour evaluations depends on whether the trial has as a goal
the response rate or the time to an event (progression/death).
If ‘time to an event’ (e.g. time to progression, disease-free
survival, progression-free survival) is the main endpoint of
the study, then routine scheduled re-evaluation of protocol
speciﬁed sites of disease is warranted. In randomised com-
parative trials in particular, the scheduled assessments
should be performed as identiﬁed on a calendar schedule
(for example: every 6–8 weeks on treatment or every 3–4
months after treatment) and should not be affected by delays
in therapy, drug holidays or any other events that might lead
to imbalance in a treatment arm in the timing of disease
assessment.
4.6.
Conﬁrmatory measurement/duration of response
4.6.1.
Conﬁrmation
In non-randomised trials where response is the primary end-
point, conﬁrmation of PR and CR is required to ensure re-
sponses identiﬁed are not the result of measurement error.
This will also permit appropriate interpretation of results in
the context of historical data where response has traditionally
required conﬁrmation in such trials (see the paper by Bogaerts
et al. in this Special Issue10). However, in all other circum-
stances, i.e. in randomised trials (phase II or III) or studies
where stable disease or progression are the primary endpoints,
conﬁrmation ofresponseis notrequiredsince itwillnotaddva-
lue to theinterpretationoftrial results.However, eliminationof
the requirement for response conﬁrmation may increase the
importance of central review to protect against bias, in partic-
ular in studies which are not blinded.
In the case of SD, measurements must have met the SD
criteria at least once after study entry at a minimum interval
(in general not less than 6–8 weeks) that is deﬁned in the
study protocol.
4.6.2.
Duration of overall response
The duration of overall response is measured from the time
measurement criteria are ﬁrst met for CR/PR (whichever is ﬁrst
recorded) until the ﬁrst date that recurrent or progressive dis-
ease is objectively documented (taking as reference for progres-
sive disease the smallest measurements recorded on study).
The duration of overall complete response is measured
from the time measurement criteria are ﬁrst met for CR until
the ﬁrst date that recurrent disease is objectively documented.
4.6.3.
Duration of stable disease
Stable disease is measured from the start of the treatment (in
randomised trials, from date of randomisation) until the crite-
ria for progression are met, taking as reference the smallest
sum on study (if the baseline sum is the smallest, this is the
reference for calculation of PD).
The clinical relevance of the duration of stable disease var-
ies in different studies and diseases. If the proportion of pa-
tients achieving stable disease for a minimum period of time
is an endpoint of importance in a particular trial, the protocol
should specify the minimal time interval required between
two measurements for determination of stable disease.
Note: The duration of response and stable disease as well as
theprogression-free survivalareinﬂuencedby thefrequencyof
follow-up after baseline evaluation. It is not in the scope of this
guideline to deﬁne a standard follow-up frequency. The fre-
quency should take into account many parameters including
disease types and stages, treatment periodicity and standard
practice. However, these limitations of the precision of the
measured endpoint should be taken into account if compari-
sons between trials are to be made.
4.7.
Progression-free survival/proportion progression-free
4.7.1.
Phase II trials
This guideline is focused primarily on the use of objective re-
sponse endpoints for phase II trials. In some circumstances, ‘re-
sponse rate’ may not be the optimal method to assess the
potential anticancer activity of new agents/regimens. In such
cases ‘progression-free survival’ (PFS) or the ‘proportion pro-
gression-free’ at landmark time points, might be considered
appropriate alternatives to provide an initial signal of biologic
effect of new agents. It is clear, however, that in an uncontrolled
trial, these measures are subject to criticism since an appar-
ently promising observation may be related to biological factors
such as patient selectionand not theimpactof theintervention.
Thus, phase II screening trials utilising these endpoints are best
designed with a randomised control. Exceptions may exist
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where the behaviour patterns of certain cancers are so consis-
tent (and usually consistently poor), that a non-randomised
trial is justiﬁable (see for example van Glabbeke et al.20). How-
ever, in these cases it will be essential to document with care
the basis for estimating the expected PFS or proportion progres-
sion-free in the absence of a treatment effect.
4.7.2.
Phase III trials
Phase III trials in advanced cancers are increasingly designed
to evaluate progression-free survival or time to progression as
the primary outcome of interest. Assessment of progression
is relatively straightforward if the protocol requires all pa-
tients to have measurable disease. However, restricting entry
to this subset of patients is subject to criticism: it may result
in a trial where the results are less likely to be generalisable if,
in the disease under study, a substantial proportion of pa-
tients would be excluded. Moreover, the restriction to entry
will slow recruitment to the study. Increasingly, therefore, tri-
als allow entry of both patients with measurable disease as
well as those with non-measurable disease only. In this cir-
cumstance, care must be taken to explicitly describe the ﬁnd-
ings which would qualify for progressive disease for those
patients without measurable lesions. Furthermore, in this set-
ting, protocols must indicate if the maximum number of re-
corded target lesions for those patients with measurable
disease may be relaxed from ﬁve to three (based on the data
found in Bogaerts et al.10 and Moskowitz et al.11). As found in
the ‘special notes on assessment of progression’, these guide-
lines offer recommendations for assessment of progression
in this setting. Furthermore, if available, validated tumour mar-
ker measures of progression (as has been proposed for ovarian
cancer) may be useful to integrate into the deﬁnition of pro-
gression. Centralised blinded review of imaging studies or of
source imaging reports to verify ‘unequivocal progression’
may be needed if important drug development or drug ap-
proval decisions are to be based on the study outcome. Finally,
as noted earlier, because the date of progression is subject to
ascertainment bias, timing of investigations in study arms
should be the same. The article by Dancey et al. in this special
issue21 provides a more detailed discussion of the assessment
of progression in randomised trials.
4.8.
Independent review of response and progression
For trials where objective response (CR + PR) is the primary end-
point, and in particular where key drug development deci-
sions are based on the observation of a minimum number of
responders, it is recommended that all claimed responses be
reviewed by an expert(s) independent of the study. If the study
is a randomised trial, ideally reviewers should be blinded to
treatment assignment. Simultaneous review of the patients’
ﬁles and radiological images is the best approach.
Independent review of progression presents some more
complex issues: for example, there are statistical problems
with the use of central-review-based progression time in
place of investigator-based progression time due to the poten-
tial introduction of informative censoring when the former
precedes the latter. An overview of these factors and other
lessons learned from independent review is provided in an
article by Ford et al. in this special issue.22
4.9.
Reporting best response results
4.9.1.
Phase II trials
When response is the primary endpoint, and thus all patients
must have measurable disease to enter the trial, all patients
included in the study must be accounted for in the report of
the results, even if there are major protocol treatment devia-
tions or if they are not evaluable. Each patient will be assigned
one of the following categories:
1. Complete response
2. Partial response
3. Stable disease
4. Progression
5. Inevaluable for response: specify reasons (for example: early
death, malignant disease; early death, toxicity; tumour
assessments not repeated/incomplete; other (specify)).
Normally, all eligible patients should be included in the
denominator for the calculation of the response rate for phase
II trials (in some protocols it will be appropriate to include all
treated patients). It is generally preferred that 95% two-sided
conﬁdence limits are given for the calculated response rate.
Trial conclusions should be based on the response rate for
all eligible (or all treated) patients and should not be based
on a selected ‘evaluable’ subset.
4.9.2.
Phase III trials
Response evaluation in phase III trials may be an indicator
of the relative anti-tumour activity of the treatments eval-
uated and is almost always a secondary endpoint. Ob-
served differences in response rate may not predict the
clinically relevant therapeutic beneﬁt for the population
studied. If objective response is selected as a primary end-
point for a phase III study (only in circumstances where a
direct relationship between objective tumour response and
a clinically relevant therapeutic beneﬁt can be unambigu-
ously demonstrated for the population studied), the same
criteria as those applying to phase II trials should be used
and all patients entered should have at least one measur-
able lesion.
In those many cases where response is a secondary end-
point and not all trial patients have measurable disease, the
method for reporting overall best response rates must be
pre-speciﬁed in the protocol. In practice, response rate may
be reported using either an ‘intent to treat’ analysis (all ran-
domised patients in the denominator) or an analysis where
only the subset of patients with measurable disease at
baseline are included. The protocol should clearly specify
how response results will be reported, including any subset
analyses that are planned.
The original version of RECIST suggested that in phase III
trials one could write protocols using a ‘relaxed’ interpreta-
tion of the RECIST guidelines (for example, reducing the num-
ber of lesions measured) but this should no longer be done
since these revised guidelines have been amended in such a
way that it is clear how these criteria should be applied for
all trials in which anatomical assessment of tumour response
or progression are endpoints.
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Appendix I. Summary of major changes RECIST 1.0 to RECIST 1.1
RECIST 1.0
RECIST 1.1
Rationale
Reference in special issue
(if applicable)
Minimum size measurable
lesions
CT: 10 mm spiral
CT 10 mm; delete reference to
spiral scan
Most scans used have 5 mm or less slice
thickness Clearer to give instruction based on
slice interval if it is greater than 5 mm
20 mm non-spiral
Clinical: 20 mm
Clinical: 10 mm (must be
measurable with calipers)
Caliper measurement will make this reliable
Lymph node: not mentioned
CT:
Since nodes are normal structure need to deﬁne
pathological enlargement. Short axis is most
sensitive
Schwartz et al.15
P15 mm short axis for target
P10–<15 mm for non-target
<10 mm is non-pathological
Special considerations on
lesion measurability
–
Notes included on bone
lesions, cystic lesions
Clarify frequently asked questions
Overall tumour burden
10 lesions (5 per organ)
5 lesions (2 per organ)
Data warehouse analysis shows no loss of
information if lesion number reduced from 10 to
5. A maximum of 2 lesions per organ yields
sufﬁcient representation per disease site
Bogaerts et al.10
Response criteria target
disease
CR lymph node not mentioned
CR lymph nodes must be
<10 mm short axis
In keeping with normal size of nodes
Schwartz et al.15
PD 20% increase over smallest sum on
study or new lesions
PD 20% increase over smallest
sum on study (including
baseline if that is smallest) and
at least 5 mm increase or new
lesions
Clariﬁcation that if baseline measurement is
smaller than any on study measurement, it is
reference against which PD is assessed
5 mm absolute increase to guard against over
calling PD when total sum is very small and 20%
increase is within measurement error
Response criteria non-target
disease
‘unequivocal progression’ considered as PD
More detailed description of
‘unequivocal progression’ to
indicate that it should not
normally trump target disease
status. It must be
representative of overall
disease status change, not a
single lesion increase
Confusion with RECIST 1.0 where some were
considering PD if ‘increase’ in any non-target
lesion, even when target disease is stable or
responding
New lesions
–
New section on New lesions
To provide guidance on when a lesion is
considered new (and thus PD)
Overall response
Table integrated target and non-target
lesions
Two tables: one integrating
target and non-target and the
other of non-target only
To account for the fact that RECIST criteria are
now being used in trials where PFS is the
endpoint and not all patients have measurable
(target) disease at baseline
Dancey et al.21
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RECIST 1.0
RECIST 1.1
Rationale
Reference in special issue
(if applicable)
Special notes:
Frequently asked questions on these topics
How to assess and measure
lymph nodes
CR in face of residual tissue
Discussion of ‘equivocal’
progression
Conﬁrmatory measure
For CR and PR: criteria
must be met again 4
weeks after initial
documentation
Retain this requirement ONLY
for
non-randomised trials with
primary endpoint of response
Data warehouse shows that response rates
rise when conﬁrmation is eliminated, but
the only circumstance where this is
important is in trials where there is no
concurrent comparative control and where
this measure is the primary endpoint
Bogaerts et al.10
Progression-free survival
General comments only
More speciﬁc comments on
use of PFS (or proportion
progression-free) as
phase II endpoint
Increasing use of PFS in phase III trials
requires guidance on assessment of PD in
patients with non-measurable disease
Dancey et al.21
Greater detail on PFS
assessment in phase III trials
Reporting of response
results
9 categories suggested for
reporting phase II results
Divided into phase II and phase
III
Simpliﬁes reporting and clariﬁes how to
report phase II and III data consistently
9 categories collapsed into 5
In phase III, guidance given
about reporting response
Response in phase III
trials
More relaxed guidelines
possible if protocol speciﬁed
This section removed and
referenced in section
above: no need to have
different criteria for phase II
and III
Simpliﬁcation of response assessment by
reducing number of lesions and eliminating
need for conﬁrmation in randomised
studies where response is not the primary
endpoint makes separate ‘rules’
unnecessary
Imaging appendix
Appendix I
Appendix II: updated with
detailed guidance on
use of MRI, PET/CT
Evolving use of newer modalities addressed.
Enhanced guidance in response to frequent
questions and from radiology review
experience
Other practical guidance
included
New appendices
Appendix I: comparison of
RECIST 1.0 and 1.1
Appendix III: frequently asked
questions
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Conﬂict of interest statement
None declared.
Acknowledgements
The RECIST Working Group would like to thank the following
organisations which made data bases available to us in order
to perform the analyses which informed decisions about
changes to this version of the criteria: Amgen; AstraZeneca;
Breast Cancer International Research Group (BCIRG); Bristol-
Myers
Squibb; European
Organisation for
Research and
Treatment of Cancer (EORTC) Breast Cancer Group and Gas-
trointestinal
Group;
Erasmus
University
Medical
Center,
Rotterdam, The Netherlands; Genentech; Pﬁzer; RadPharm;
Roche; SanoﬁAventis.
We would also like to thank the following individuals from
academic, government, and pharmaceutical organisations for
providing helpful comments on an earlierdraft of these revised
guidelines: Ohad Amit, Phil Murphy, Teri Crofts and Janet Be-
gun, GlaxoSmithKline, USA; Laurence H. Baker, Southwest
Oncology Group, USA; Karla Ballman, Mayo Clinic, USA;
Charles Baum, Darrel Cohen, and Mary Ashford Collier, Pﬁzer,
USA; Gary J. Becker, American Board of Radiology, Tucson,
USA; Jean-Yves Blay, University Claude Pertrand, Lyon France;
Renzo Canetta, Bristol-Myers Squibb, USA; David Chang, Am-
gen Inc., USA; Sandra Chica, Perceptive Informations Inc. (PAR-
EXEL),
USA;
Martin
Edelman,
University
of
Maryland
Greenbaum Cancer Centre, USA; Gwendolyn Fyfe, Genentech,
USA; Bruce Giantonio, Eastern Cooperative Oncology Group,
USA; Gary Gordon, Abbott Pharmaceuticals, USA; Ronald Gott-
lieb, Roswell Park Cancer Institute, USA; Simon Kao, University
of Iowa College of Medicine, USA; Wasaburo Koizumi, Kitasato
University, Japan; Alessandro Riva, Novartis Pharmaceuticals,
USA; Wayne Rackhoff, Ortho Biotech Oncology Research and
Development, USA; Nagahiro Saijo, President Japanese Society
of Medical Oncology, Japan; Mitchell Schnall American College
of Radiology Imaging Network, USA; Yoshik Shimamura, PAR-
EXEL International Inc., Japan; Rajeshwari Sridhara, Centre
for Drug Evaluation and Research, Food and Drug Administra-
tion, USA; Andrew Stone, Alan Barge, AstraZeneca, United
Kingdom; Orhan Suleiman, Centre for Drug Evaluation and Re-
search, Food and Drug Administration, USA; Daniel C. Sullivan,
Duke University Medical Centre, USA; Masakazu Toi, Kyoto
University, Japan; Cindy Welsh, Centre for Drug Evaluation
and Research, Food and Drug Administration, USA.
Finally, the RECIST Working Group would like to thank indi-
vidualswho were not permanent members of the group (which
are all acknowledged as co-authors) but who attended working
group meetings from time to time and made contributions to
the total process over the past 7 years: Richard Pazdur, Food
and Drug Administration, USA; Francesco Pignatti, European
Medicines Agency, London, UK.
Appendix II.
Speciﬁcations for standard
anatomical radiological imaging
These protocols for image acquisition of computed tomogra-
phy (CT) and magnetic resonance imaging (MRI) are recom-
mendations intended for patients on clinical trials where
RECIST assessment will be performed. Standardisation of
imaging requirements and image acquisition parameters is
ideal to allow for optimal comparability of subjects within a
study and results between studies. These recommendations
are designed to balance optimised image acquisition proto-
cols with techniques that should be feasible to perform glob-
ally at imaging facilities in all types of radiology practices.
These guidelines are not applicable to functional imaging
techniques or volumetric assessment of tumour size.
Scanner quality control is highly recommended and should
follow
standard
manufacturer
and
facility
maintenance
schedules using commercial phantoms. It is likely that for RE-
CIST unidimensional measurements this will be adequate to
produce reproducible measurements. Imaging quality control
for CT includes an analysis of image noise and uniformity and
CT number as well as spatial resolution. The frequency of
quality control analysis is also variable and should focus on
clinically relevant scanning parameters. Dose analysis is al-
ways important and the use of imaging should follow the
ALARA principle, ‘As Low As Reasonably Achievable’, which
refers to making every reasonable effort to maintain radiation
exposures as far below the dose limits as possible.
Speciﬁc.notes
Chest X-ray measurement of lesions surrounded by pulmon-
ary
parenchyma
is
feasible,
but
not
preferable
as
the
measurement represents a summation of densities. Further-
more, there is poor identiﬁcation of new lesions within the
chest on X-ray as compared with CT. Therefore, measure-
ments of pulmonary parenchymal lesions as well as medias-
tinal disease are optimally performed with CT of the chest.
MRI of the chest should only be performed in extenuating cir-
cumstances. Even if IV contrast cannot be administered (for
example, in the situation of allergy to contrast), a non-con-
trast CT of the chest is still preferred over MRI or chest X-ray.
CT scans: CT scans of the chest, abdomen, and pelvis should
be contiguous throughout all the anatomic region of interest.
As a general rule, the minimum size of a measurable lesion at
baseline should be no less than double the slice thickness and
also have a minimum size of 10 mm (see below for minimum
size when scanners have a slice thickness more than 5 mm).
While the precise physics of lesion size and partial volume
averaging is complex, lesions smaller than 10 mm may be dif-
ﬁcult to accurately and reproducibly measure. While this rule
is applicable to baseline scans, as lesions potentially decrease
in size at follow-up CT studies, they should still be measured.
Lesions which are reported as ‘too small to measure’ should
be assigned a default measurement of 5 mm if they are still
visible.
The most critical CT image acquisition parameters for opti-
mal tumour evaluation using RECIST are anatomic coverage,
contrast administration, slice thickness, and reconstruction interval.
a. Anatomic coverage: Optimal anatomic coverage for most
solid tumours is the chest, abdomen and pelvis. Cover-
age should encompass all areas of known predilection
for metastases in the disease under evaluation and
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should additionally investigate areas that may be
involved based on signs and symptoms of individual
patients. Because a lesion later identiﬁed in a body part
not scanned at baseline would be considered as a new
lesion representing disease progression, careful consid-
eration should begiven to the extent of imaging coverage
at baseline and at subsequent follow-up time points.
This will enable better consistency not only of tumour
measurements but also identiﬁcation of new disease.
b. IV contrast administration: Optimal visualisation and
measurement of metastases in solid tumours requires
consistent administration (dose and rate) of IV contrast
as well as timing of scanning. Typically, most abdomi-
nal imaging is performed during the portal venous
phase and (optimally) about the same time frame after
injection on each examination (see Fig. 1 for impact of
different phase of IV contrast on lesion measurement).
Most solid tumours may be scanned with a single
phase after administration of contrast. While triphasic
CT scans are sometimes performed on other types of
vascular tumours to improve lesion conspicuity, for
consistency and uniformity, we would recommend tri-
phasic
CT
for
hepatocellular
and
neuroendocrine
tumours for which this scanning protocol is generally
standard of care, and the improved temporal resolution
of the triphasic scan will enhance the radiologists’ abil-
ity to consistently and reproducibly measure these
lesions. The precise dose and rate of IV contrast is
dependent upon the CT scanning equipment, CT acqui-
sition protocol, the type of contrast used, the available
venous
access
and
the
medical
condition
of
the
patient. Therefore, the method of administration of
intravenous contrast agents is variable. Rather than
try to institute rigid rules regarding methods for
administering contrast agents and the volume injected,
it is appropriate to suggest that an adequate volume of
a suitable contrast agent should be given so that the
metastases are demonstrated to best effect and a con-
sistent method is used on subsequent examinations for
any given patient (ideally, this would be speciﬁed in
the protocol or for an institution). It is very important
that the same technique be used at baseline and on fol-
low-up examinations for a given patient. This will
greatly enhance the reproducibility of the tumour mea-
surements. If prior to enrolment it is known a patient is
not able to undergo CT scans with IV contrast due to
allergy
or
renal
insufﬁciency,
the
decision
as
to
whether a non-contrast CT or MRI (with or without IV
contrast) should be used to evaluate the subject at
baseline and follow-up should be guided by the tumour
type under investigation and the anatomic location of
the disease. For patients who develop contraindica-
tions to contrast after baseline contrast CT is done,
the decision as to whether non-contrast CT or MRI
(enhanced or non-enhanced) should be performed
should also be based on the tumour type, anatomic
location of the disease and should be optimised to
allow for comparison to the prior studies if possible.
Each case should be discussed with the radiologist to
determine if substitution of these other approaches is
possible and, if not, the patient should be considered
not evaluable from that point forward. Care must be
taken in measurement of target lesions on a different
modality and interpretation of non-target disease or
new lesions, since the same lesion may appear to have
a different size using a new modality (see Fig. 2 for a
comparison of CT and MRI of the same lesion). Oral
contrast is recommended to help visualise and differ-
entiate structures in the abdomen.
c. Slice thickness and reconstruction interval: RECIST measure-
ments may be performed at most clinically obtained
slice thicknesses. It is recommended that CT scans be
performed at 5 mm contiguous slice thickness or less
and indeed this guideline presumes a minimum 5 mm
thickness in recommendations for measurable lesion
deﬁnition. Indeed, variations in slice thickness can have
an impact on lesion measurement and on detection of
new lesions. However, consideration should also be
given for minimising radiation exposure. With these
parameters, a minimum 10 mm lesion is considered
measurable at baseline. Occasionally, institutions may
perform medically acceptable scans at slice thicknesses
greater than 5 mm. If this occurs, the minimum size of
measurable lesions at baseline should be twice the slice
Fig. 1 – Difference in measurement/visualisation with different phases of IV contrast administration. Hypervascular
metastases imaged in the arterial phase (left) and the portal venous phase (right). Note that the number of lesions visible
differs greatly between the two phases of contrast administration as does any potential lesion measurement. Consistent CT
scan acquisition, including phase of contrast administration, is important for optimal and reproducible tumour
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thickness of the baseline scans. Most contemporary CT
scanners are multidetector which have many imaging
options for these acquisition parameters.23 The equip-
ment vendor and scanning manual should be reviewed
if there are any speciﬁc system questions.
d. Alternative contrast agents: There are a number of other,
new contrast agents, some organ speciﬁc.24 They may
be used as part of patient care for instance, in liver
lesion assessment, or lymph node characterisation25,
but should not as yet be used in clinical trials.
FDG-PET has gained acceptance as a valuable tool for
detecting, staging and restaging several malignancies. Criteria
for incorporating (or substituting) FDG-PET into anatomical
assessment of tumour response in phase II trials are not yet
available, though much research is ongoing. Nevertheless,
FDG-PET is being used in many drug development trials both
as a tool to assess therapeutic efﬁcacy and also in assessment
of progression. If FDG-PET scans are included in a protocol, by
consensus, an FDG uptake period of 60 min prior to imaging
has been decided as the most appropriate for imaging of pa-
tients with malignancy.26 Whole-body acquisition is impor-
tant since this allows for sampling of all areas of interest
and can assess if new lesions have appeared thus determining
the possibility of interval progression of disease. Images from
the base of the skull to the level of the mid-thigh should be ob-
tained 60 min post injection. PET camera speciﬁcations are
variable and manufacturer speciﬁc, so every attempt should
be made to use the same scanner, or the same model scanner,
for serial scans on the same patient. Whole-body acquisitions
can be performed in either 2- or 3-dimensional mode with
attenuation correction, but the method chosen should be con-
sistent across all patients and serial scans in the clinical trial.
PET/CT scans: Combined modality scanning such as with
PET–CT is increasingly used in clinical care, and is a modal-
ity/technology that is in rapid evolution; therefore, the recom-
mendations in this paper may change rather quickly with
time. At present, low dose or attenuation correction CT por-
tions of a combined PET–CT are of limited use in anatomically
based efﬁcacy assessments and it is therefore suggested that
they should not be substituted for dedicated diagnostic con-
trast enhanced CT scans for anatomically based RECIST mea-
surements. However, if a site can document that the CT
performed as part of a PET–CT is of identical diagnostic qual-
ity to a diagnostic CT (with IV and oral contrast) then the CT
portion of the PET–CT can be used for RECIST measurements.
Note, however, that the PET portion of the CT introduces addi-
tional data which may bias an investigator if it is not routinely
or serially performed.
Ultrasound examinations should not be used in clinical trials
to measure tumour regression or progression of lesions be-
cause the examination is necessarily subjective and operator
dependent. The reasons for this are several: Entire examina-
tions cannot be reproduced for independent review at a later
date, and it must be assumed, whether or not it is the case,
that the hard-copy ﬁlms available represent a true and accu-
rate reﬂection of events. Furthermore, if, for example, the
only measurable lesion is in the para-aortic region of the
abdomen and if gas in the bowel overlies the lesion, the lesion
will not be detected because the ultrasound beam cannot
penetrate the gas. Accordingly, the disease staging (or restag-
ing for treatment evaluation) for this patient will not be
accurate.
While evaluation of lesions by physical examination is also
of limited reproducibility, it is permitted when lesions are
superﬁcial, at least 10 mm size, and can be assessed using
calipers. In general, it is preferred if patients on clinical trials
have at least one lesion that is measurable by CT. Other skin
or palpable lesions may be measured on physical examina-
tion and be considered target lesions.
Use of MRI remains a complex issue. MRI has excellent
contrast, spatial and temporal resolution; however, there
are many image acquisition variables involved in MRI, which
greatly impact image quality, lesion conspicuity and mea-
surement. Furthermore, the availability of MRI is variable
globally. As with CT, if an MRI is performed, the technical
speciﬁcations of the scanning sequences used should be
optimised for the evaluation of the type and site of disease.
Furthermore, as with CT, the modality used at follow-up
should be the same as was used at baseline and the lesions
should be measured/assessed on the same pulse sequence.
Generally, axial imaging of the abdomen and pelvis with T1
and T2 weighted imaging along with gadolinium enhanced
imaging should be performed. The ﬁeld of view, matrix,
number of excitations, phase encode steps, use of fat sup-
pression and fast sequences should be optimised for the spe-
Fig. 2 – CT versus MRI of same lesions showing apparent ‘progression’ due only to differing method of measurement.
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ciﬁc body part being imaged as well as the scanner utilised. It
is beyond the scope of this document or appendix to pre-
scribe speciﬁc MRI pulse sequence parameters for all scan-
ners, body parts and diseases. Ideally, the same type of
scanner should be used and the image acquisition protocol
should be followed as closely as possible to prior scans. Body
scans should be performed with breath-hold scanning tech-
niques if possible.
Selection of target lesions: In general, the largest lesions rep-
resentative of involved organs (up to a maximum of two per
organ and ﬁve total) are selected to follow as target lesions.
However, in some cases, the largest lesions may not be easily
measured and are not suitable for follow-up because of their
conﬁguration. In these cases, identiﬁcation of the largest most
reproducible lesions is advised. Fig. 3 provides an illustrative
example where the largest lesion is not the most reproducible
and another lesion is better to select and follow:
Measurement of lesions
The longest diameter of selected lesions should be measured
in the plane in which the images were acquired. For body CT,
this is the axial plane. In the event isotropic reconstructions
are performed, measurements can be made on these recon-
structed images; however, it should be cautioned that not
all radiology sites are capable of producing isotropic recon-
structions. This could lead to the undesirable situation of
measurements in the axial plane at one assessment point
and in a different plane at a subsequent assessment. There
are some tumours, for instance paraspinal lesions, which
are better measured in the coronal or sagittal plane. It would
be acceptable to measure these lesions in these planes if the
reconstructions in those planes were isotropic or the images
were acquired with MRI in those planes. Using the same plane
of evaluation, the maximal diameter of each target lesion
should always be measured at subsequent follow-up time
points even if this results in measuring the lesion at a differ-
ent slice level or in a different orientation or vector compared
with the baseline study. Software tools that calculate the
maximal diameter for a perimeter of a tumour may be em-
ployed and may even reduce variability.
The only exception to the longest diameter rule is lymph
node measurement. Because malignant nodes are identiﬁed
by the length of their short axis, this is the guide used to
determine not only whether they are pathological but is also
the dimension measured for adding into the sum of target le-
sions. Fig. 4 illustrates this point: the large arrow identiﬁes a
malignant node: the shorter perpendicular axis is P15 mm
and will be recorded. Close by (small arrow) there is a normal
node: note here the long axis is greater than 10 mm but the
short axis is well below 10 mm. This node should be consid-
ered non-pathological.
If a lesion disappears and reappears at a subsequent time
point it should continue to be measured. However, the pa-
tient’s response at the point in time when the lesion reap-
pears will depend upon the status of his/her other lesions.
For example, if the patient’s tumour had reached a CR status
and the lesion reappeared, then the patient would be consid-
ered PD at the time of reappearance. In contrast, if the tumour
status was a PR or SD and one lesion which had disappeared
then reappears, its maximal diameter should be added to the
sum of the remaining lesions for a calculated response: in
other words, the reappearance of an apparently ‘disappeared’
single lesion amongst many which remain is not in itself en-
Fig. 3 – Largest lesion may not be most reproducible: most reproducible should be selected as target. In this example, the
primary gastric lesion (circled at baseline and at follow-up in the top two images) may be able to be measured with thin
section volumetric CT with the same degree of gastric distention at baseline and follow-up. However, this is potentially
challenging to reproduce in a multicentre trial and if attempted should be done with careful imaging input and analysis. The
most reproducible lesion is a lymph node (circled at baseline and at follow-up in the bottom two images).
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ough to qualify for PD: that requires the sum of all lesions to
meet the PD criteria. The rationale for such a categorisation is
based upon the realisation that most lesions do not actually
‘disappear’ but are not visualised because they are beyond
the resolving power of the imaging modality employed.
The identiﬁcation of the precise boundary deﬁnition of a
lesion may be difﬁcult especially when the lesion is embed-
ded in an organ with a similar contrast such as the liver, pan-
creas, kidney, adrenal or spleen. Additionally, peritumoural
oedema may surround a lesion and may be difﬁcult to distin-
guish on certain modalities between this oedema and actual
tumour. In fact, pathologically, the presence of tumour cells
within the oedema region is variable. Therefore, it is most
critical that the measurements be obtained in a reproducible
manner from baseline and all subsequent follow-up time-
points. This is also a strong reason to consistently utilise
the same imaging modality.
When lesions ‘fragment’, the individual lesion diameters
should be added together to calculate the target lesion
sum. Similarly, as lesions coalesce, a plane between them
may be maintained that would aid in obtaining maximal
diameter measurements of each individual lesion. If the le-
sions have truly coalesced such that they are no longer sep-
arable, the vector of the longest diameter in this instance
should be the maximal longest diameter for the ‘merged
lesion’.
Progression of non-target lesions
To achieve ‘unequivocal progression’ there must be an overall
level of substantial worsening in non-target disease that is of
a magnitude that, even in the presence of SD or PR in target
disease, the treating physician would feel it important to
change therapy. Examples of unequivocal progression are
shown in Figs. 5 and 6.
Fig. 5 – Example of unequivocal progression in non-target lesions in liver.
Fig. 6 – Example of unequivocal progression in non-target lesion (nodes).
Fig. 4 – Lymph node assessment: large arrow illustrates a
pathological node with the short axis shown as a solid line
which should be measured and followed. Small arrow illus-
trates a non-pathological node which has a short axis
<10 mm.
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Appendix III. Frequently asked questions
Question
Answer
What should be done if several unique lesions at
baseline become conﬂuent at a follow-up
evaluation?
Measure the longest diameter of the conﬂuent mass and record to add into the sum of
the longest diameters
How large does a new lesion have to be to count
as progression? Does any small subcentimetre
lesion qualify, or should the lesion be at least
measurable?
New lesions do not need to meet ‘measurability criteria’ to be considered valid. If it is
clear on previous images (with the same technique) that a lesion was absent then its
deﬁnitive appearance implies progression. If there is any doubt (because of the
techniques or conditions) then it is suggested that treatment continue until next
scheduled assessment when, generally, all should be clear. Either it gets bigger and the
date of progression is the date of the ﬁrst suspicion, or it disappears and one may then
consider it an artefact with the support of the radiologists
How should one lesion be measured if on
subsequent exams it is split into two?
Measure the longest diameter of each lesion and add this into the sum
Does the deﬁnition of progression depend on
the status of all target lesions or only one?
As per the RECIST 1.1 guideline, progression requires a 20% increase in the sum of
diameters of all target lesions AND a minimum absolute increase of 5 mm in the sum
Are RECIST criteria accepted by regulatory
agencies?
Many cooperative groups and members of pharma were involved in preparing RECIST
1.0 and have adopted them. The FDA was consulted in their development and supports
their use, though they don’t require it. The European and Canadian regulatory
authorities also participated and the RECIST criteria are now integrated in the European
note for guidance for the development of anticancer agents. Many pharmaceutical
companies are also using them. RECIST 1.1 was similarly widely distributed before
publication
What is the criterion for a measurable lesion if
the CT slice thickness is >5 mm?
RECIST 1.1 recommends that CT scans have a maximum slice thickness of 5 mm and the
minimum size for a measurable lesion is twice that: 10 mm (even if slice thickness is
<5 mm). If scanners with slice thickness >5 mm are used, the minimum lesion size must
have a longest diameter twice the actual slice thickness
What should we record when target lesions
become so small they are below the 10 mm
‘measurable’ size?
Target lesion measurability is deﬁned at baseline. Thereafter, actual measurements,
even if <10 mm, should be recorded. If lesions become very small, some radiologists
indicate they are ‘too small to measure’. This guideline advises that when this occurs, if
the lesion is actually still present, a default measurement of 5 mm should be applied. If
in fact the radiologist believes the lesion has gone, a default measurement of 0 mm
should be recorded
If a patient has several lesions which have
decreased in size to meet PR criteria and one
has actually disappeared, does that patient have
PD if the ‘disappeared’ lesion reappears?
Unless the sum meets the PD criteria, the reappearance of a lesion in the setting of PR (or
SD) is not PD. The lesion should simply be added into the sum.
If the patients had had a CR, clearly reappearance of an absent lesion would qualify for
PD
When measuring the longest diameter of target
lesions in response to treatment, is the same
axis that was used initially used subsequently,
even if there is a shape change to the lesion that
may have produced a new longest diameter?
The longest diameter of the lesion should always be measured even if the actual axis is
different from the one used to measure the lesion initially (or at different time point
during follow-up)
The only exception to this is lymph nodes: as per RECIST 1.1 the short axis should
always be followed and as in the case of target lesions, the vector of the short axis may
change on follow-up
Target lesions have been selected at baseline
and followed but then one of these target
lesions then becomes non-evaluable (i.e.
different technique used)
What may be done in such cases is one of the following:
What is the effect this has on the other target
lesions and the overall response?
(a) If the patient is still being treated, call the centre to be sure that future evaluations are
done with the baseline technique so at least SOME courses are fully evaluable
(b) If that is not possible, check if there IS a baseline exam by the same technique which
was used to follow patients...in which case if you retrieve the baseline measures from
that technique you retrieve the lesion evaluability
(c) If neither (a) nor (b) is possible then it is a judgement call about whether you delete
the lesion from all forms or consider the impact of the lesion overall is so important that
its being non-evaluable makes the overall response interpretation inevaluable without
it. Such a decision should be discussed in a review panel
It is NOT recommended that the lesion be included in baseline sums and then excluded
from follow-up sums since this biases in favour of a response
(continued on next page)
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Appendix III – continued
Question
Answer
What if a single non-target lesion cannot be reviewed, for
whatever reason; does this negate the overall assessment?
Sometimes the major contribution of a single non-target lesion may be in
the setting of CR having otherwise been achieved: failure to examine one
non-target in that setting will leave you unable to claim CR. It is also
possible that the non-target lesion has undergone such substantial
progression that it would override the target disease and render patient
PD. However, this is very unlikely, especially if the rest of the measurable
disease is stable or responding
A patient has a 32% decrease in sum cycle 2, a 28% decrease cycle
4 and a 33% decrease cycle 6. Does conﬁrmation of PR have to
take place in sequential scans or is a case like this conﬁrmed PR?
It is not infrequent that tumour shrinkage hovers around the 30% mark.
In this case, most would consider PR to have been conﬁrmed looking at
this overall case. Had there been two or three non-PR observations
between the two time point PR responses, the most conservative
approach would be to consider this case SD
In the setting of a breast cancer neoadjuvant study, would
mammography not be used to assess lesions? Is CT preferred in
this setting?
Neither CT nor mammography are optimal in this setting. MRI is the
preferred modality to follow breast lesions in a neoadjuvant setting
A patient has a lesion measurable by clinical exam and by CT
scan. Which should be followed?
CT scan. Always follow by imaging if that option exists since it can be
reviewed and veriﬁed
A lesion which was solid at baseline has become necrotic in the
centre. How should this be measured?
The longest diameter of the entire lesion should be followed. Eventually,
necrotic lesions which are responding to treatment decrease in size. In
reporting the results of trials, you may wish to report on this
phenomenon if it is seen frequently since some agents (e.g. angiogenesis
inhibitors) may produce this effect
If I am going to use MRI to follow disease, what is minimum size
for measurability?
MRI may be substituted for contrast enhanced CT for some sites, but not
lung. The minimum size for measurability is the same as for CT (10 mm)
as long as the scans are performed with slice thickness of 5 mm and no
gap. In the event the MRI is performed with thicker slices, the size of a
measurable lesion at baseline should be two times the slice thickness. In
the event there are inter-slice gaps, this also needs to be considered in
determining the size of measurable lesions at baseline
Can PET–CT be used with RECIST?
At present, the low dose or attenuation correction CT portion of a
combined PET–CT is not always of optimal diagnostic CT quality for use
with RECIST measurements. However, if your site has documented that
the CT performed as part of a PET–CT is of the same diagnostic quality as
a diagnostic CT (with IV and oral contrast) then the PET–CT can be used
for RECIST measurements. Note, however, that the PET portion of the CT
introduces additional data which may bias an investigator if it is not
routinely or serially performed
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