An Endometrial Cancer Study for Women With Recurrent or Persistent Endometrial Cancer

Study Overview
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Brief Summary
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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 recurrent or persistent endometrial cancer, who have failed progestin monotherapy or who have been identified as Progesterone Receptor (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 ImmunoHistoChemistry (IHC) testing. There are two treatment periods and a follow-up period within the study.

Detailed Description
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Treatment Period 1 (Progestin Monotherapy): During Treatment Period 1, all subjects determined to be PrR positive will receive progestin monotherapy, megestrol acetate, for up to 24 weeks. Subjects will have an MRI or CT scan after 12 and 24 weeks of progestin monotherapy, with response to treatment being assessed according to RECIST 1.1 criteria. All subjects that achieve disease control confirmed by tumor assessment after Treatment Period 1, will be ineligible to enter Treatment Period 2. These subjects will be terminated from the trial and treated according to local standards of practice, which may include continued progestin therapy. Subjects determined to be PrR negative at Screening will not enroll into Treatment Period 1. These subjects will enroll directly into Treatment Period 2. 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 at the conclusion of Treatment Period 1 will enter Treatment Period 2 of the study. During Treatment Period 2, subjects will receive Sodium Cridanimod in combination with continued progestin treatment, megestrol acetate. Subjects will receive treatment until disease progression as defined according to RECIST 1.1 criteria, with response assessments performed at 12-week intervals. Follow-up Period: Once subjects progress during Treatment Period 2, they will return for a Safety Follow-up Visit 4 weeks following the last treatment, and then continue to be followed for an additional 12-month period for overall survival.

Official Title
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A Phase 2, Single Arm, Two Period Study of Sodium Cridanimod in Conjunction With Progestin Therapy in Patients With Endometrial Carcinoma

Conditions
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Endometrial Cancer

Intervention / Treatment
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* Drug: Sodium Cridanimod
* Drug: progestin therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female patients 18 years of age or older; Histologically confirmed serous carcinoma or endometrioid type of endometrial carcinoma (histological documentation of recurrence is not required); Recurrent or persistent progressive disease which is refractory to curative therapy or established treatments and cannot be treated with surgery or radiotherapy; Measurable disease, as defined by RECIST 1.1 criteria; 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; Availability of archived tumor tissue sample that can be used for assessment of PrR status by the central laboratory; GOG (Gynecologic Oncology Group) performance status 0-2 (refer to Appendix A); Calculated Glomerular filtration rate ≥ 50 mL/min; Total bilirubin ≤ 2.5 times upper limit of normal (ULN); AST ≤ 2.5 times ULN (≤ 5 times ULN for patients with liver metastases); Alkaline phosphatase ≤ 2.5 times ULN (≤ 5 times ULN for patients with liver metastases); Albumin ≥ 3.0 mg/dL; Ability to take oral medication; Patients able to understand the nature of the study and who are willing to give written informed consent; 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: Mixed histology of the tumor or evidence of tumor histology other than serous carcinoma or endometrioid type of endometrial carcinoma; Concurrent systemic corticosteroid therapy; Concurrent oral contraceptive use / Women of childbearing potential not using highly effective means of contraception; Pregnancy confirmed by pregnancy test / Lactating women; Prior therapy with hormonal progestin agents; Patients who are candidates for treatment with standard chemotherapy agents (there is no limit to the number of lines of chemotherapy); History of blood clot; History of known bleeding disorder (i.e. disseminated intravascular coagulation or clotting factor deficiency); Major surgery within 4 weeks prior to the start of the study; Patients with clinically significant illnesses which, according to the Investigator, could compromise participation in the study; 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. Known hypersensitivity or idiosyncratic reaction to any of the study drugs (Sodium Cridanimod, megestrol acetate, lidocaine) and excipients; Patients with known brain metastases; Patients currently receiving any other investigational agents; Patients currently receiving any other anticancer therapies; Participation in any other clinical study within the last 4 weeks prior to the start of the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Phase 2, Single Arm, Two Period Study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sodium Cridanimod & progestin therapy<br>Sodium Cridanimod and progestin therapy (megestrol acetate) combination | Drug: Sodium Cridanimod<br>* 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.<br>Drug: progestin therapy<br>* The study will investigator the use of progestin therapy in conjunction with Sodium Cridanimod<br>* Other names: megestrol acetate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Disease Control (ODC) as Determined by Radiographic Imaging Measurements | Subjects in the Full Analysis Set (FAS) population will be assessed for ODC. The FAS population includes those subjects all treated in TP2 who either undergo a CT or MRI scan with tumor assessment at 12 weeks (i.e. they have not discontinued treatment prior to 12 weeks) or those who have discontinued TP2 prior to 12 weeks solely due to documented disease progression. Radiographic disease progression and responses will be defined using RECIST 1.1 criteria: Control Response(CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions. The appearance of new lesions is also considered progression. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD | During TP2 Every 12 weeks, until disease progression up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | The best overall response was the best response recorded from the start of Treatment Period 2 until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started).To be assigned a status of CR or PR, tumor measurements were confirmed by repeat assessment performed at least four weeks after the criteria for response are first met. Best Overall Response (OR) was determined based on the following combinations of repeat assessments: CR + CR = CR, CR + PR= SD, PD or PR, CR + SD =SD, CR+ PD = SD, CR + NEW= SD, PR + CR= PR, PR + PR= PR, PR+ SD= SD, PR + PD= SD, PR+ NEW = SD. | 24 months | 
| Progression-free Survival (PFS) | Progressive Disease was assessed using RECIST Guideline (version 1.1) whereas at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. Progression-free Survival (PFS) was defined as the duration of time from initiation of Treatment Period 2 (Day 0) until disease progression or death from any cause, whichever occurs first. For the purpose of analysis of PFS, subjects with an unknown response were censored. | 24 months | 
| Duration of Stable Disease | Stable Disease (SD) was assessed using RECIST Guideline (version 1.1) whereas neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Duration of Stable Disease was defined as the duration of time from initiation of Treatment Period 2 (Day 0) until the criteria for disease progression were first met. For the purpose of analysis of Duration of SD, subjects who died before documented progressive disease were censored. | 24 months | 
| Overall Survival (OS) | Once disease progression was documented in Treatment Period 2, subjects returned for the Safety Follow-up Visit four (4) weeks following the last treatment and continued to be followed for an additional 12-month period for overall survival. Overall Survival (OS) was defined as the duration of time from initiation of Treatment Period 2 (Day 0) until the subject's death from any cause. For the purpose of analysis of OS, if a subject is alive at the date of last contact the subject was censored at that date of contact. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Endometrial cancer, Recurrent or persistent endometrial carcinoma, Progesterone Receptor Negative, Sodium Cridanimod