Endometrial Cancer
Conditions
Keywords
Endometrial cancer, Recurrent or persistent endometrial carcinoma, Progesterone Receptor Negative, Sodium Cridanimod
Brief summary
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
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.
Interventions
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.
DRUGprogestin therapy
The study will investigator the use of progestin therapy in conjunction with Sodium Cridanimod
Sponsors
Xenetic Biosciences, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase 2, Single Arm, Two Period Study
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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 (Gynecologic Oncology Group) performance status 0-2 (refer to Appendix A); 8. Calculated 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; 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 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Disease Control (ODC) as Determined by Radiographic Imaging Measurements | During TP2 Every 12 weeks, until disease progression up to 24 months | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | 24 months | 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. |
| Progression-free Survival (PFS) | 24 months | 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. |
| Duration of Stable Disease | 24 months | 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. |
| Overall Survival (OS) | 12 months | 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. |
Countries
United States
Participant flow
Pre-assignment details
Subjects with PrR (+) tumors began in Treatment Period 1 receiving only Progestin Monotherapy. If PrR (+) subjects had disease progression they continued into Treatment Period 2 receiving Progestin and Sodium Cridanimod therapy. Subjects with PrR (-) tumors enrolled directly into Treatment Period 2.
Participants by arm
| Arm | Count |
|---|---|
| PrR (+) Subjects Subjects noted at Screening to have PrR (+) tumors were enrolled into Treatment Period 1 (TP1) receiving Progestin Monotherapy. Subjects noted to have Progressive Disease rolled into Treatment Period 2 (TP2) and received combination therapy of Sodium Cridanimod and Progestin. PrR (+) subjects that had Disease Control or Stable Disease after 24 weeks of Monotherapy treatment were not eligible to participate in TP2 and were discontinued. | 16 |
| PrR(-) Subjects Subjects with PrR(-) tumors at screening will be enrolled directly into Treatment Period 2 (TP2) receiving combination therapy of Sodium Cridanimod and Progestin. | 9 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Progestin Monotherapy | Adverse Event | 1 | 0 |
| Progestin Monotherapy | Death | 1 | 0 |
| Progestin Monotherapy | Stable Disease | 8 | 0 |
| Safety Follow Up | Transfer of care to hospice | 1 | 0 |
| Safety Follow Up | Withdrawal by Subject | 2 | 1 |
| Sodium Cridanimod & Progestin Therapy | Adverse Event | 0 | 2 |
| Sodium Cridanimod & Progestin Therapy | Disease Progression | 6 | 5 |
| Sodium Cridanimod & Progestin Therapy | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | PrR (+) Subjects | PrR(-) Subjects | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 8 Participants | 7 Participants | 15 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 2 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 8 Participants | 24 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 2 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 7 Participants | 16 Participants |
| Region of Enrollment United States | 16 participants | 9 participants | 25 participants |
| Sex: Female, Male Female | 16 Participants | 9 Participants | 25 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 16 | 4 / 15 |
| other Total, other adverse events | 13 / 16 | 12 / 15 |
| serious Total, serious adverse events | 5 / 16 | 2 / 15 |
Outcome results
Primary
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
Time frame: During TP2 Every 12 weeks, until disease progression up to 24 months
Population: A total of 15 subjects entered Treatment Period 2, which included the 9 subjects who were PrR negative and the 6 subjects who were PrR positive and completed Treatment Period 1, and received treatment with Intramuscular (IM) sodium cridanimod in combination with oral progestin (megestrol acetate). 2 subjects were unevaluable and withdrew prior to meeting criteria for inclusion in FAS population.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sodium Cridanimod & Progestin Therapy | Overall Disease Control (ODC) as Determined by Radiographic Imaging Measurements | Progressive Disease | 8 Participants |
| Sodium Cridanimod & Progestin Therapy | Overall Disease Control (ODC) as Determined by Radiographic Imaging Measurements | Stable Disease | 5 Participants |
| Sodium Cridanimod & Progestin Therapy | Overall Disease Control (ODC) as Determined by Radiographic Imaging Measurements | Partial Response | 0 Participants |
| Sodium Cridanimod & Progestin Therapy | Overall Disease Control (ODC) as Determined by Radiographic Imaging Measurements | Control Response | 0 Participants |
Secondary
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.
Time frame: 24 months
Population: A total of 15 subjects entered Treatment Period 2, which included the 9 subjects who were PrR negative and the 6 subjects who were PrR positive and completed Treatment Period 1, and received treatment with IM sodium cridanimod in combination with oral progestin (megestrol acetate). Four (4) subjects withdrew from the study and 8 subjects did not meet the criteria to be evaluable for duration of SD.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sodium Cridanimod & Progestin Therapy | Duration of Stable Disease | 001-15-01 | 168 days |
| Sodium Cridanimod & Progestin Therapy | Duration of Stable Disease | 001-48-01 | 166 days |
| Sodium Cridanimod & Progestin Therapy | Duration of Stable Disease | 001-45-01 | 144 days |
Secondary
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.
Time frame: 24 months
Population: A total of 15 subjects entered Treatment Period 2, which included the 9 subjects who were PrR negative and the 6 subjects who were PrR positive and completed Treatment Period 1, and received treatment with IM sodium cridanimod in combination with oral progestin (megestrol acetate). Four (4) subjects withdrew from the study prior to meeting evaluable criteria for ORR
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sodium Cridanimod & Progestin Therapy | Objective Response Rate (ORR) | Progressive Disease | 8 Participants |
| Sodium Cridanimod & Progestin Therapy | Objective Response Rate (ORR) | Stable Disease | 3 Participants |
| Sodium Cridanimod & Progestin Therapy | Objective Response Rate (ORR) | Control Response | 0 Participants |
| Sodium Cridanimod & Progestin Therapy | Objective Response Rate (ORR) | Partial Response | 0 Participants |
Secondary
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.
Time frame: 12 months
Population: Fifteen (15) subjects who participated in Treatment Period 2 were eligible to be followed for OS; however, 4 of these subjects elected to not participate in the Follow-up Period because of withdrawal of consent (3 subjects) or other (1 subject, subject transferred to hospice). For the 11 subjects who participated in the Follow-up Period for OS, the time (in number of days) from the date of discontinuation to the time of death or last contact for survival information ranged from 32 to 457 days.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sodium Cridanimod & Progestin Therapy | Overall Survival (OS) | 001-15-01 | 529 days |
| Sodium Cridanimod & Progestin Therapy | Overall Survival (OS) | 001-30-01 | 411 days |
| Sodium Cridanimod & Progestin Therapy | Overall Survival (OS) | 001-39-05 | 473 days |
| Sodium Cridanimod & Progestin Therapy | Overall Survival (OS) | 001-45-02 | 541 days |
| Sodium Cridanimod & Progestin Therapy | Overall Survival (OS) | 001-48-01 | 490 days |
| Sodium Cridanimod & Progestin Therapy | Overall Survival (OS) | 001-01-03 | 77 days |
| Sodium Cridanimod & Progestin Therapy | Overall Survival (OS) | 001-39-07 | 32 days |
| Sodium Cridanimod & Progestin Therapy | Overall Survival (OS) | 001-39-08 | 394 days |
| Sodium Cridanimod & Progestin Therapy | Overall Survival (OS) | 001-43-01 | 65 days |
| Sodium Cridanimod & Progestin Therapy | Overall Survival (OS) | 001-45-01 | 386 days |
| Sodium Cridanimod & Progestin Therapy | Overall Survival (OS) | 001-47-03 | 438 days |
Secondary
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.
Time frame: 24 months
Population: A total of 15 subjects entered Treatment Period 2, which included the 9 subjects who were PrR negative and the 6 subjects who were PrR positive and completed Treatment Period 1, and received treatment with IM sodium cridanimod in combination with oral progestin (megestrol acetate). Four (4) subjects withdrew from the study prior to meeting evaluable criteria for PFS.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sodium Cridanimod & Progestin Therapy | Progression-free Survival (PFS) | 001-15-01 | 168 days |
| Sodium Cridanimod & Progestin Therapy | Progression-free Survival (PFS) | 001-30-01 | 54 days |
| Sodium Cridanimod & Progestin Therapy | Progression-free Survival (PFS) | 001-39-05 | 85 days |
| Sodium Cridanimod & Progestin Therapy | Progression-free Survival (PFS) | 001-45-02 | 85 days |
| Sodium Cridanimod & Progestin Therapy | Progression-free Survival (PFS) | 001-48-01 | 166 days |
| Sodium Cridanimod & Progestin Therapy | Progression-free Survival (PFS) | 001-01-03 | 31 days |
| Sodium Cridanimod & Progestin Therapy | Progression-free Survival (PFS) | 001-39-07 | 32 days |
| Sodium Cridanimod & Progestin Therapy | Progression-free Survival (PFS) | 001-39-08 | 88 days |
| Sodium Cridanimod & Progestin Therapy | Progression-free Survival (PFS) | 001-43-01 | 60 days |
| Sodium Cridanimod & Progestin Therapy | Progression-free Survival (PFS) | 001-45-01 | 144 days |
| Sodium Cridanimod & Progestin Therapy | Progression-free Survival (PFS) | 001-47-03 | 73 days |