a phase 2 single arm
untitled h2

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
a phase 2 single arm
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.  
| 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 |  
| 3.4.Inclusion Criteria .                                                                                                   |                                                                                                   |
|----------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------|
| 3.5.Exclusion Criteria .                                                                                                   |                                                                                                   |
| 3.6.Discontinuation Criteria for Individual Subjects .................................................................. 33 |                                                                                                   |
| 3.7.Patient Requirements .                                                                                                 |                                                                                                   |
| 3.8.Subject Identification .                                                                                               |                                                                                                   |
| STUDY DRUG …                                                                                                               |                                                                                                   |
| 4.                                                                                                                         | 4.1.Description of Study Drugs                                                                    |
| 4.1.1 Sodium Cridanimod                                                                                                    |                                                                                                   |
| 4.1.2 Megestrol acetate                                                                                                    |                                                                                                   |
| 4.1.3 Lidocaine Hydrochloride                                                                                              |                                                                                                   |
| 4.2.Preparation of Sodium Cridanimod .                                                                                     |                                                                                                   |
| 4.3.Study Drug Handling                                                                                                    |                                                                                                   |
| TREATMENTS AND EVALUATION                                                                                                  |                                                                                                   |
| 5.                                                                                                                         | 5.1.Dosing and Administration of Study Drugs and Other Medications                                |
| 5.1.1. Dose/Dose Regimen and Administration ............................................................... 35             |                                                                                                   |
| 5.1.1 Megestrol acetate                                                                                                    |                                                                                                   |
| 5.1.1.2 Sodium Cridanimod                                                                                                  |                                                                                                   |
| Dose Modifications                                                                                                         |                                                                                                   |
| 5.1.2.                                                                                                                     | Duration of Therapy                                                                               |
| 5.1.3.                                                                                                                     | 5.1.3.1   Treatment Period 1                                                                      |
| 5.1.3.2  Treatment Period 2                                                                                                |                                                                                                   |
| 5.1.4. Duration of Follow-up                                                                                               |                                                                                                   |
| 5.1.5. Subject Compliance                                                                                                  |                                                                                                   |
| 5.2.Demographics and Baseline Characteristics ................................................................ 37          |                                                                                                   |
| 5.2.1. Demographics                                                                                                        |                                                                                                   |
| 5.2.2. Medical History                                                                                                     |                                                                                                   |
| 5.3.Assessment of PrR Status at Screening                                                                                  |                                                                                                   |
| 5.4.Visit Schedule and Required Study Procedures ......................................................... 37              |                                                                                                   |
| 5.4.1. Screening                                                                                                           |                                                                                                   |
| Treatment                                                                                                                  |                                                                                                   |
| 5.4.2.                                                                                                                     |                                                                                                   |
| 5.4.3.   Follow-up Period                                                                                                  |                                                                                                   |
| 5.5.Efficacy Assessments                                                                                                   |                                                                                                   |
| Visual Tumor Examination                                                                                                   |                                                                                                   |
| 5.5.1.                                                                                                                     | Tumor Imaging and Measurement (CT/MRI) ....................................................... 45 |
| 5.5.2.                                                                                                                     |                                                                                                   |
| 5.5.3.                                                                                                                     | Gynecologic Oncology Group (GOG) Performance Status ............................... 45            |  
| 5.6.Assessment of Response .                              |                                                                                                     |
|-----------------------------------------------------------|-----------------------------------------------------------------------------------------------------|
| 5.6.1. Measurable Disease Definitions                     |                                                                                                     |
| 5.6.2. Definitions of Response                            |                                                                                                     |
| 5.6.3. Evaluations of a Subject's Best Overall Response   |                                                                                                     |
| 5.7.Safety Assessments                                    |                                                                                                     |
| 5.7.1. Concomitant Medication                             |                                                                                                     |
| Vital Signs                                               |                                                                                                     |
| 5.7.2.                                                    | Laboratory Assessments .                                                                            |
| 5.7.3.                                                    | 5.7.3.1.Hematology .                                                                                |
| 5.7.3.2.Serum Chemistry                                   |                                                                                                     |
| 5.7.3.3.Urinalysis                                        |                                                                                                     |
| Pregnancy Test .                                          |                                                                                                     |
| 5.7.4.                                                    | Physical Examination                                                                                |
| 5.7.5.                                                    |                                                                                                     |
| 5.7.6. Electrocardiogram                                  |                                                                                                     |
| 5.7.7. Patient Diary                                      |                                                                                                     |
| 5.8.Optional Sub-Study Procedures                         |                                                                                                     |
| 5.8.1. Optional Pharmacokinetic (PK) Sub-Study            |                                                                                                     |
| 5.9.Adverse Events and Other Safety Aspects               |                                                                                                     |
| 5.9.1.                                                    | Definition of Adverse Events                                                                        |
| 5.9.2.                                                    | Definition of Serious Adverse Events .                                                              |
| Criteria for Causal Relationship                          |                                                                                                     |
| 5.9.3.                                                    |                                                                                                     |
| 5.9.4.                                                    | Criteria for Defining the Severity of an Adverse Event ......................................... 55 |
| 5.9.5.                                                    | Reporting of Serious Adverse Events (SAEs) .                                                        |
| Reporting of Deaths                                       |                                                                                                     |
| 5.9.6.                                                    |                                                                                                     |
| 5.9.7. Procedure in Case of Pregnancy                     |                                                                                                     |
| TERMINATION OF THE CLINICAL STUDY                         |                                                                                                     |
| 6.                                                        | STATISTICAL METHODOLOGY                                                                             |
| 7.                                                        | 7.1.Sample Size                                                                                     |
| 7.2.Analysis Sets                                         |                                                                                                     |
| 7.2.1. Safety Population                                  |                                                                                                     |
| 7.2.2. Full Analysis Set (FAS)                            |                                                                                                     |
| 7.2.3. Per Protocol Set (PPS)                             |                                                                                                     |
| 7.3.Demographics and Other Baseline Characteristics       |                                                                                                     |
| 7.4.Analysis of Efficacy .                                |                                                                                                     |
| 7.4.1. Analysis of Primary Objective .                    |                                                                                                     |
| 7.4.2. Analysis of Secondary and Translational Objectives |                                                                                                     |  
| 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   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
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| 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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |  
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)
A Phase 2, Single Arm, Two Period Study of Sodium Cridanimod in Conjunction with Progestin Therapy in Patients with Endometrial Carcinoma
a phase 2 single arm
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 statements regarding confidentiality.  
Signed: ___________________________________________  
  
  
  
Date: _____________________ 02 Jan 2018  
  
A Phase 2, Single Arm, Two Period Study of Sodium Cridanimod in Conjunction with Progestin Therapy in Patients with Endometrial Carcinoma  
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.
a phase 2 single arm
principal investigator

| Signature:              | Date   |
|-------------------------|--------|
| Printed Name:  Address: |        |  
| 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   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| 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                                                      |  
| 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                                                                                                                                                                                                                   |  
| dose administrations and possible pharmaceutical interaction between  Sodium Cridanimod and megestrol acetate.   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |
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| 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). |  
| -                                                                                                                                                                                                                                                            | 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; |  
| 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. |  
| -                                                                                                                                                                                                                                                                                  | 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                                                                                                                                                                                                                                                                 | An ECG will be obtained during Screening.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |
| (ECG)                                                                                                                                                                                                                                                                              | 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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |  
| 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, |                                                                                                 |  
| 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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Up to 50 study sites in the US and Europe are planned for enrollment.                                                                                                                                                                                                                                                                                                                                                                                                                              |                |
| Locations) Planned  Estimated Time                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | First subject enrolled:                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | September 2017 |
| Schedule                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Recruitment completed: September 2018  Last subject completed the study: January 2021                                                                                                                                                                                                                                                                                                                                                                                                              |                |
study design and assessment schedule
table 1 screening schedule of

| 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. |            |  
| Subjects Ineligible                                                                                                                                                                                                                                                                                                                                                                                                 |                            |     |     |     |         |                    |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------|-----|-----|-----|---------|--------------------|
| Treatment Period 1                                                                                                                                                                                                                                                                                                                                                                                                  | to enter TP2 or who        |     |     |     |         |                    |
| (PrR Positive Patients Only)                                                                                                                                                                                                                                                                                                                                                                                        | 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                                                                                                                                                                                                                                                                                                                                                                                                       | X C                        | X   | X   | X   | X       |                    |
| Vital Signs                                                                                                                                                                                                                                                                                                                                                                                                         | X                          | X   | X   | X   | X       |                    |
| Weight                                                                                                                                                                                                                                                                                                                                                                                                              | X C                        | X   | X   | X   | X       |                    |
| Performance Status                                                                                                                                                                                                                                                                                                                                                                                                  | X C                        | X   | X   | X   | X       |                    |
| CBC w/ diff, platelets                                                                                                                                                                                                                                                                                                                                                                                              | X C                        | X   | X   | X   | X       |                    |
| Serum chemistryA                                                                                                                                                                                                                                                                                                                                                                                                    | X C                        | X   | X   | X   | X       |                    |
| C                                                                                                                                                                                                                                                                                                                                                                                                                   | X                          | X   | X   | X   |         |                    |
| eGFR                                                                                                                                                                                                                                                                                                                                                                                                                | X                          |     |     |     |         |                    |
| Urinalysis                                                                                                                                                                                                                                                                                                                                                                                                          | X                          |     |     |     |         |                    |
| Urine Pregnancy TestB                                                                                                                                                                                                                                                                                                                                                                                               | X                          |     |     |     |         |                    |
| ECG                                                                                                                                                                                                                                                                                                                                                                                                                 | X H                        | X H | X H | X H | X       |                    |
| Blood Draw (for PK sub-study)G                                                                                                                                                                                                                                                                                                                                                                                      | X G                        |     |     |     |         |                    |
| Assessment of Adverse Events                                                                                                                                                                                                                                                                                                                                                                                        | X                          | X   | X   | X   | X       |                    |
| Imaging (CT/MRI)                                                                                                                                                                                                                                                                                                                                                                                                    | X                          | X D |     |     |         |                    |
| Tumor Assessment (using RECIST criteria)                                                                                                                                                                                                                                                                                                                                                                            | X                          | X D |     |     |         |                    |
| 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. |                            |     |     |     |         |                    |
study design and assessment schedule
table 2 tp1 schedule of

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.  
| Treatment Period 2                                                                                                                                                                                                                                                                                                                                                                                 | Safety                                                                                                                                                                                       |     |     |     |     |     |     |     |     |     |     |     |               |                   |                       |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----|-----|-----|-----|-----|-----|-----|-----|-----|-----|-----|---------------|-------------------|-----------------------|
| Study Visits                                                                                                                                                                                                                                                                                                                                                                                       | 1                                                                                                                                                                                            | 2   | 3   | 4   | 5   | 6   | 7   | 8   | 9   | 10  | 11  | 12  | 13 - ?        | 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                                                                                                                                                                                                                                                                                                                                                                                             | Sodium Cridanimod is administered twice a week on either Mondays and Thursdays or                                                                                                            |     |     |     |     |     |     |     |     |     |     |     |               |                   |                       |
| Cridanimod                                                                                                                                                                                                                                                                                                                                                                                         | Tuesdays and Fridays for the duration of Treatment Period 2.                                                                                                                                 |     |     |     |     |     |     |     |     |     |     |     |               |                   |                       |
| Progestin therapy                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                                                                              |     |     |     |     |     |     |     |     |     |     |     |               |                   |                       |
| (Megestrol acetate)                                                                                                                                                                                                                                                                                                                                                                                | 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                 |                       |
| Dispensing/ReturnJ                                                                                                                                                                                                                                                                                                                                                                                 | 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                                                                                                                                                                                                                                                                                                                                                                                                | X E                                                                                                                                                                                          | X   | XE  | X   | X   | X   | X   | X   | X   | X   | X   | X   | X             | X                 |                       |
| Blood Draw (for  PK sub-study)                                                                                                                                                                                                                                                                                                                                                                     | X D                                                                                                                                                                                          | 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 | X B |     |     |     |     |     |     |     |     |     |     |               |                   |                       |
| later to confirm the presence of an objective response. Documentation (CT or MRI) must be  provided for subjects removed from study for progressive disease.                                                                                                                                                                                                                                       |                                                                                                                                                                                              |     |     |     |     |     |     |     |     |     |     |     |               |                   |                       |
| 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                                                                                                                                                                                                                                                                                                                                                                         |                                                                                                                                                                                              | X I |     |     |     |     |     |     |     |     |     |     |               |                   |                       |
| determine  survival  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) |                                                                                                                                                                                              |     |     |     |     |     |     |     |     |     |     |     |               |                   |                       |  
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.  
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
study design and assessment schedule
1. introduction 1.1. background 1.1.1.

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
study design and assessment schedule
1.1.2. progestins for the treatment

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.
study design and assessment schedule
table 4. efficacy of megestrol

| Treatment      | Overall          | Median progression free   | Median overall  survival, months   | Reference   |
|----------------|------------------|---------------------------|------------------------------------|-------------|
| response rate  | survival, months |                           |                                    |             |
| MA 800  mg/day | 24%              | 2.5                       | 7.6                                | 4           |
| MA             | NA               | NA                        | 12                                 | 5           |
| MA +           |                  |                           |                                    |             |
| Tamoxifen      | NA               | NA                        | 8.6                                | 5           |  
cancer.  
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%.  
| 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                               |
study design and assessment schedule
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.
study design and assessment schedule
1.2.1. nonclinical data relevant to

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.
study design and assessment schedule
1.2.2. clinical data relevant to

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 with progestin therapy may be most pronounced in subjects for whom progestin monotherapy demonstrates no efficacy.
study design and assessment schedule
1.3. summary of key safety

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   | Frequency of  AE based on  total Subjects  treated*   |                              |     |         |
|-------------------------------------------------------------------------|-------------------------------------------------------|------------------------------|-----|---------|
| Investigator                                                            | Total Subjects                                        |                              |     |         |
| AE Frequency                                                            |                                                       |                              |     |         |
| Adverse Event                                                           | Causality                                             | with reported                |     |         |
| per Study                                                               |                                                       |                              |     |         |
| Assessment                                                              | AE to date*                                           |                              |     |         |
| 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.  
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.  
| tolerability study in healthy subjects   | Sodium Cridanimod  500 mg i.m.  + 2% Lidocaine  hydrochloride  1 mL twice a week   |                                                          |    |
|------------------------------------------|------------------------------------------------------------------------------------|----------------------------------------------------------|----|
| Sodium Cridanimod                        |                                                                                    |                                                          |    |
| Study treatment                          | 500 mg i.m. 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.