Refractory Endometrial Adenocarcinoma, Refractory Endometrial Carcinoma, Refractory Endometrial Clear Cell Adenocarcinoma, Refractory Endometrial Endometrioid Adenocarcinoma, Refractory Endometrial Mixed Cell Adenocarcinoma, Refractory Endometrial Serous Adenocarcinoma, Refractory Endometrial Undifferentiated Carcinoma
Conditions
Brief summary
This phase II trial studies the effect of onapristone and anastrozole in treating patients with hormone receptor positive endometrial cancer that has not responded to previous treatment (refractory). Progesterone and estrogen are hormones that can cause the growth of endometrial cancer cells. Onapristone blocks the use of progesterone by the tumor cells. Anastrozole is a drug that blocks the production of estrogen in the body. Giving onapristone with anastrozole may work better than anastrozole alone in treating patients with hormone receptor positive endometrial cancer.
Detailed description
PRIMARY OBJECTIVE: I. To evaluate the activity and safety of a pure progesterone receptor (PR) antagonist, extended-release onapristone (onapristone), with anastrozole to treat women with recurrent metastatic estrogen receptor positive (ER+)/progesterone receptor positive (PR+) endometrial carcinoma. SECONDARY OBJECTIVES: I. To estimate the disease control rate (DCR). II. To describe duration of response (DOR). III. To evaluate the safety and tolerability. IV. To evaluate quality of life using the Edmonton Symptom Assessment questionnaire. EXPLORATORY OBJECTIVES: I. To characterize the ER and PR expression by immunohistochemistry (IHC) pre- and post-treatment. OUTLINE: Patients receive onapristone orally (PO) twice daily (BID) and anastrozole PO once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 24 cycles (24 months) in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for up to 1 year after last treatment administration.
Interventions
DRUGExtended-release Onapristone
Given PO
DRUGAnastrozole
Given PO
OTHERQuality-of-Life Assessment
Ancillary studies
OTHERQuestionnaire Administration
Ancillary studies
DIAGNOSTIC_TESTEstrogen Receptor Positive (Positive Estrogen Receptor; ESR Positive; ESR1 Positive; ER Positive; Estrogen Receptor Alpha Positive)
Immunohistochemistry (IHC):Integral : Tissue
DIAGNOSTIC_TESTProgesterone Receptor Positive ( PGR Positive; PR Positive)
Immunohistochemistry (IHC)
Sponsors
Thomas Jefferson University
Context Therapeutics Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age greater than or equal to 18 years old * Histologically confirmed diagnosis of endometrial cancer with ER and/or PR expression \>= 1% by IHC on archival tissue taken within the prior 3 years or new biopsy if no archival tissue is available. IHC results do not have to be from Thomas Jefferson University * Patients who have failed one prior treatment with a platinum/taxane chemotherapy regimen for management of disease \* Patients cannot have treatment with more than 2 prior lines of therapy (one line must be platinum/taxane regimen) * Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v.)1.1. Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension. Each lesion must be \>= 10 mm when measured by computed tomography (CT) or magnetic resonance imaging (MRI). Lymph nodes must be \>= 15 mm in short axis when measured by CT or MRI * Patients with the following histologic epithelial cell types are eligible: * Endometrioid adenocarcinoma * Serous adenocarcinoma * Undifferentiated carcinoma * Clear cell adenocarcinoma * Mixed epithelial carcinoma * Adenocarcinoma not otherwise specified (NOS) * Please note: patients with carcinosarcoma are ineligible for this trial * Patients must have had one prior treatment with a platinum/taxane chemotherapy regimen for management of disease * Eastern Cooperative Oncology Group (ECOG) performance status 0-1 * Must have a life expectancy of at least 12 weeks as judged by the treating physician * Females are only eligible for this study if they are postmenopausal. This is defined as meeting one of the following criteria: * S/p total abdominal hysterectomy and bilateral salpingo-oopherectomy * Patients who are in menopause is defined clinically as 12 consecutive months of amenorrhea in a woman over 55 in the absence of other biological or physiological causes OR women under the age of 55 must have a documented serum follicle stimulating hormone (FSH) level less than 40 mIU/mL. * Body weight \> 30 kg * Absolute neutrophil count 1500/ul or more * Platelets 100,000/ul or more * Hemoglobin 9 g/dl or more * Bilirubin less than or equal to 1.5 x the upper limit of normal (except subjects with Gilbert syndrome, who can have total bilirubin \< 3 mg/dl) * Endocrine and targeted therapy protocols usually enroll patients with aspartate aminotransferase (AST)/alanine aminotransferase (ALT) \< 2.5 x upper limit of normal (ULN) in patients without underlying liver metastasis and \< 5.0 x ULN in patients with underlying liver metastasis * Glomerular filtration rate (GFR) greater than or equal to 40 ml/min using the Cockcroft-Gault formula or measured creatinine clearance using 24 hours urine collection * International normalized ratio (INR) OR prothrombin time (PT) and activated partial thromboplastin time (aPTT) =\< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants * All subjects must be able to comprehend and sign a written informed consent document * Resolution of all acute toxic effects of prior therapy to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (version 5.0) grade =\< 1, with the exception of unresolved grade 2 neuropathy and grade 2 alopecia, which are allowed * Patient has recovered from any prior radiotherapy * Patients must be able to swallow tablets whole, without crushing * Be able to read and speak English
Exclusion criteria
* Concurrent or recent chemotherapy, radiotherapy, immunotherapy, or general anesthesia/major surgery within 3 weeks * History of prior hormonal therapy (i.e., megestrol acetate, tamoxifen or aromatase inhibitors) for treatment cancer within the past 2 months. Other concurrent hormonal therapy will not be allowed on this trial * Patient has a concurrent malignancy or history of invasive malignancy within 3 years of enrollment, with the exception of basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix that has completed curative therapy * If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment * Has received prior systemic anti-cancer therapy including investigational agents within 3 weeks prior to randomization * Known brain metastasis which have not been treated or showed stability for \>= 6 months * Proteinuria \> 1+ on urinalysis or \> 1 gm/24 hours (hr) * Known history of New York Heart Association stage 3 or 4 cardiac disease * A pleural or pericardial effusion of greater than or equal to grade 3 severity * Women who are pregnant or nursing * Has an active infection requiring systemic therapy * Use of any prescription medication during the prior 28 days of first onapristone dosing that the investigator judges is likely to interfere with onapristone activity; specifically strong inhibitors or inducers, or sensitive substrates of cytochrome P450 CYP3A4 * Patients may not be on a concurrent clinical trial, unless approved by investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | Up to 1 year post-treatment, up to 36 months total | Defined by the percentage of patients with tumor response (complete response \[CR\] or partial response \[PR\]) as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
| Progression-Free Survival (PFS) | From treatment until disease progression or death, up to 25 months | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate | Up to 1 year post-treatment | Defined as best overall response of CR, PR, or stable disease lasting for \>= 24 weeks, per RECIST 1.1. |
| Time to Response | up to 1 yr post treatment | Time to Response defined as time from randomization to first documented response (CR or PR) in months. |
| Duration of Response in Participants With Complete Response | From the first date of documented response to progression or death due to endometrial cancer, assessed up to 1 year post-treatment | Duration of Response (DOR) is the time from the first documented achievement of a Partial Response (PR) or Complete Response (CR) until the date of confirmed disease Progression (PD) or death due to endometrial cancer. |
| Duration of Response in Participants With Partial Response | From the first date of documented response to progression or death due to endometrial cancer, assessed up to 1 year post-treatment | Duration of Response (DOR) is the time from the first documented achievement of a Partial Response (PR) or Complete Response (CR) until the date of confirmed disease Progression (PD) or death due to endometrial cancer. |
| Quality of Life Assessed by the Edmonton Symptom Assessment System | Up to 25 months | Quality of life and pain scores are defined by the Edmonton Symptom Assessment System (ESAS) using nine subjective patient measures of well-being including pain, tiredness, nausea, depression, anxiety, drowsiness, appetite, well-being, shortness of breath. Numerical Rating Scale (NRS): Each symptom, including Pain and Well-being (which reflects Quality of Life), is rated on a 0 to 10 scale. Pain Score: 0 = No pain, 10 = Worst possible pain. Quality of Life / Well-being Score: 0 = Best possible feeling of well-being (i.e., best QoL), 10 = Worst possible feeling of well-being (i.e., worst QoL). ESAS scores were collected over the course of treatment and follow-up. Results represent the mean score for each symptom averaged across all available assessments for each participant. Higher scores reflect greater symptom severity. Scores are reported as means with standard deviations. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORTommy Buchanan, MD
Thomas Jefferson University
Participant flow
Recruitment details
Participants were recruited between January, 2021 and March, 2023, a total of 18 patients were screened across two sites, with 14 ultimately enrolled.
Pre-assignment details
18 patients were screened for eligibility based on protocol defined inclusion/exclusion criteria. Eligibility was determined by histologically confirmed diagnosis of endometrial cancer with ER and/or PR expression ≥1% by IHC on archival tissue taken within the prior 3 years or new biopsy if no archival tissue is available, measurable disease as defined by RECIST v.1.1., and ECOG Performance status 0-1. Data from 14 patients were included in the FAS.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 67 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 10 Participants |
| Region of Enrollment United States | 14 participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 14 |
| other Total, other adverse events | 11 / 14 |
| serious Total, serious adverse events | 3 / 14 |
Outcome results
None listed