Clinical Trials /

Onapristone and Anastrozole in Refractory Estrogen and Progesterone Positive Endometrial Cancer

NCT04719273

Description:

The purpose of this research is to evaluate the combination treatment of onapristone, a drug that inhibits the production of progesterone, with anastrozole, a drug that inhibits the production of estrogen, for women with refractory hormone receptor positive (estrogen and progesterone receptor positive) endometrial cancer. Currently, Anastrozole is approved for the treatment of recurrent endometrial cancer with a response rate of 9%. Our hypothesis is that the combination of estrogen and progesterone inhibition will help improve the response rate in patients with estrogen receptor positive and progesterone receptor positive endometrial cancer.

Related Conditions:
  • Endometrial Clear Cell Adenocarcinoma
  • Endometrial Mixed Adenocarcinoma
  • Endometrial Serous Adenocarcinoma
  • Endometrial Undifferentiated Carcinoma
  • Endometrioid Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Onapristone and Anastrozole in Refractory Estrogen and Progesterone Positive Endometrial Cancer
  • Official Title: A Phase II Clinical Trial Evaluating the Combination of Onapristone With Anastrozole for Women With Refractory Hormone Receptor Positive Endometrial Cancer

Clinical Trial IDs

  • ORG STUDY ID: 20P.829
  • NCT ID: NCT04719273

Conditions

  • Endometrial Cancer

Interventions

DrugSynonymsArms
Onapristone, Extended-Release FormulationER OnapristoneSingle Arm
Anastrozole 1mgArimidexSingle Arm

Purpose

The purpose of this research is to evaluate the combination treatment of onapristone, a drug that inhibits the production of progesterone, with anastrozole, a drug that inhibits the production of estrogen, for women with refractory hormone receptor positive (estrogen and progesterone receptor positive) endometrial cancer. Currently, Anastrozole is approved for the treatment of recurrent endometrial cancer with a response rate of 9%. Our hypothesis is that the combination of estrogen and progesterone inhibition will help improve the response rate in patients with estrogen receptor positive and progesterone receptor positive endometrial cancer.

Detailed Description

      Endometrial cancer is the most common gynecologic malignancy in the United States with an
      incidence that continues to increase each year. More than 60,000 women were diagnosed with
      endometrial cancer in 2018 and this disease contributes to more than 10,000 deaths annually.
      Unopposed estrogen production and obesity are the most common risk factors for the
      development of endometrial cancer; both late stage disease and histologic subtype portends to
      a poor prognosis with a five-year survival of only 20%. In the second line setting, cytotoxic
      chemotherapy has a 13% response rate and hormonal therapy with anastrozole has a response
      rate of 9%. For a minority of patients with MSI-high endometrial cancer (about 30% of
      patients), pembrolizumab is a therapeutic option and results in an overall response rate of
      39% in 149 patients across 15 tumor types with 78% of responses lasting greater than 6 months
      and has led to FDA approval of this single agent in tissue agnostic cases. Megesterol acetate
      is approved in the second line setting with response rates as high as 24% in conjunction with
      tamoxifen, but is not commonly used due to poor tolerance and high risk of thrombosis. The
      majority of patients with recurrent endometrial cancer have limited therapeutic options and
      the development of second line therapies that result in improved response is an unmet
      clinical need. Using targeted hormonal treatment may present potential opportunities for
      improved treatment outcomes for these women.
    

Trial Arms

NameTypeDescriptionInterventions
Single ArmExperimentalPatients receive onapristone PO BID and anastrozole PO 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.
  • Onapristone, Extended-Release Formulation
  • Anastrozole 1mg

Eligibility Criteria

        Inclusion Criteria:

          -  1. Age greater than or equal to 18 years old 2. 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.

             3. Patients who have failed front line therapy with Carboplatin/Paclitaxel 4.
             Measurable disease as defined by RECIST 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 ≥10mm when measured by CT or MRI. Lymph nodes must be ≥10mm in short
             axis when measured by CT or MRI 5. Patients with the following histologic epithelial
             cell types are eligible:

               1. Endometrioid adenocarcinoma

               2. Serous adenocarcinoma

               3. Undifferentiated carcinoma

               4. Clear cell adenocarcinoma

               5. Mixed epithelial carcinoma

               6. Adenocarcinoma not otherwise specified (NOS)

               7. Please note: patients with carcinosarcoma are ineligible for this trial. 6.
                  Patients must have had one prior treatment with a platinum/taxane chemotherapy
                  regimen for management of disease.

                  7. They cannot receive chemotherapy, immunotherapy or other endocrine therapy
                  concurrently.

                  8. ECOG Performance status 0-1. 9. Must have a life expectancy of at least 12
                  weeks as judged by the treating physician.

                  10. Postmenopausal females are only eligible for this study. This is defined as
                  being s/p hysterectomy or patients who are in menopause is defined clinically as
                  12 months of amenorrhea in a woman over 45 in the absence of other biological or
                  physiological causes. In addition, women under the age of 55 must have a
                  documented serum follicle stimulating hormone (FSH) level less than 40 mIU/mL.

                  11. Body weight >30 kg 12. Adequate organ function:

               1. Absolute neutrophil count 1500/µl or more;

               2. Platelets 100,000/µl or more,

               3. Hemoglobin 9 g/dl or more;

               4. 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);

               5. Endocrine and targeted therapy protocols usually enroll patients with AST/ALT
                  <2.5 x ULN in patients without underlying liver metastasis and <5.0 x ULN in
                  patients with underlying liver metastasis.

               6. GFR greater than or equal to 40 ml/min using the Cockcroft-Gault formula or
                  measured creatinine clearance using 24 hours urine collection

               7. International normalized ratio (INR) OR prothrombin time (PT) and activated
                  partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving
                  anticoagulant therapy as long as PT or aPTT is within therapeutic range of
                  intended use of anticoagulants 13. All subjects must be able to comprehend and
                  sign a written informed consent document.

                  14. Resolution of all acute toxic effects of prior therapy to NCI CTCAE (Version
                  5.0) Grade ≤ 1, with the exception of unresolved Grade 2 neuropathy and Grade 2
                  alopecia, which are allowed 15. Patient has recovered from any prior radiotherapy
                  16. Patients must be able to swallow tablets whole, without crushing 17. Be able
                  to read and speak English.

                  Exclusion Criteria:

          -  1. Concurrent or recent chemotherapy, radiotherapy, immunotherapy, or general
             anesthesia/major surgery within 3 weeks.

             2. History of prior hormonal therapy (i.e., megesterol acetate, tamoxifen or aromatase
             inhibitors) for treatment cancer within the past 2 months. Other concurrent hormonal
             therapy will not be allowed on this trial.

             3. Patients with concurrent second malignancy (other than non-melanoma skin cancer or
             curatively treated in situ carcinoma).

             4. Patients must have recovered from all known or expected toxicities from previous
             treatment and passed a treatment-free "washout" period of 3 weeks before starting this
             program. However, Grade 1 or 2 neuropathy and alopecia are acceptable.

             5. If participant received major surgery, they must have recovered adequately from the
             toxicity and/or complications from the intervention prior to starting study treatment.

             6. Has received prior systemic anti-cancer therapy including investigational agents
             within 3weeks prior to randomization.

             7. Participants must have recovered from all AEs due to previous therapies to ≤Grade 1
             or baseline. Participants with ≤Grade 2 neuropathy may be eligible.

             8. Known brain metastasis which have not been treated or showed stability for ≥ 6
             months 9. Proteinuria >1+ on urinalysis or >1 gm/24hr. 10. Known history of New York
             Heart Association stage 3 or 4 cardiac disease. 11. A pleural or pericardial effusion
             of moderate severity or worse. 12. Women who are pregnant or nursing. 13. Women who
             are pre-menopausal. 14. Has an active infection requiring systemic therapy. 15. 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.
             Investigators should consult the following table of clinically-relevant products
             http://medicine.iupui.edu/CLINPHARM/ddis/clinical-table.

             16. Patients may not be on a concurrent clinical trial, unless approved by
             Investigator.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate (ORR)
Time Frame:Up to 1 year post-treatment
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Disease Control Rate
Time Frame:Up to 1 year post-treatment
Safety Issue:
Description:Disease control rate (DCR) defined as best overall response of CR, PR or SD lasting for ≥ 24 weeks, per RECIST 1.1
Measure:Time to Response
Time Frame:From randomization to first documented response (CR or PR) in months, assessed up to 1 year post-treatment
Safety Issue:
Description:Time to Response defined as time from randomization to first documented response (CR or PR) in months
Measure:Duration of Response
Time Frame:From the first date of documented response to progression or death due to endometrial cancer, assessed up to 1 year post-treatment
Safety Issue:
Description:Duration of Response defined as time between the first date of documented response to progression or death due to endometrial cancer
Measure:Type, frequency and severity of adverse events and laboratory abnormalities
Time Frame:Up to 30 days post-treatment
Safety Issue:
Description:Adverse events will be graded for severity according to the Common Terminology Criteria for Adverse Events version 5.0.
Measure:Quality of Life and pain score
Time Frame:Up to 1 year post-treatment
Safety Issue:
Description:Quality of life and pain scores are defined by the Edmonton Symptom Assessment System using nine subjective patient measures of well-being including pain, tiredness, nausea, depression, anxiety, drowsiness, appetite, well-being, shortness of breath.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Thomas Jefferson University

Last Updated

March 29, 2021