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Onapristone and Anastrozole in Refractory Estrogen and Progesterone Positive Endometrial Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04719273
Recruitment Status : Recruiting
First Posted : January 22, 2021
Last Update Posted : June 4, 2021
Information provided by (Responsible Party):
Thomas Jefferson University

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.

Condition or disease Intervention/treatment Phase
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 Drug: Extended-release Onapristone Drug: Anastrozole Other: Quality-of-Life Assessment Other: Questionnaire Administration Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 25 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Clinical Trial Evaluating the Combination of Onapristone With Anastrozole for Women With Refractory Hormone Receptor Positive Endometrial Cancer
Actual Study Start Date : January 28, 2021
Estimated Primary Completion Date : December 15, 2022
Estimated Study Completion Date : December 15, 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Anastrozole

Arm Intervention/treatment
Experimental: Treatment (onapristone, anastrozole)
Patients 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.
Drug: Extended-release Onapristone
Given PO
Other Name: ER Onapristone

Drug: Anastrozole
Given PO

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Other: Questionnaire Administration
Ancillary studies

Primary Outcome Measures :
  1. Objective response rate (ORR) [ Time Frame: Up to 1 year post-treatment ]
    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.

  2. Progression-Free Survival (PFS) [ Time Frame: At 4 months ]
    4 month PFS is defined as a binary endpoint, from first dose of onapristone and anastrozole to 4 months of therapy as "confirmed progression-free" or "not progression-free" (including cancer progression or censored subjects). Will use the date of first documented disease progression or recurrence, as assessed by using RECIST 1.1 criteria, or death due to any cause, whichever occurs first.

Secondary Outcome Measures :
  1. Disease Control Rate [ Time Frame: Up to 1 year post-treatment ]
    Disease control rate (DCR) defined as best overall response of CR, PR or SD lasting for ≥ 24 weeks, per RECIST 1.1

  2. Time to Response [ Time Frame: From randomization to first documented response (CR or PR) in months, assessed up to 1 year post-treatment ]
    Time to Response defined as time from randomization to first documented response (CR or PR) in months

  3. 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 ]
    Duration of Response defined as time between the first date of documented response to progression or death due to endometrial cancer

  4. Type, frequency and severity of adverse events and laboratory abnormalities [ Time Frame: Up to 30 days post-treatment ]
    Adverse events will be graded for severity according to the Common Terminology Criteria for Adverse Events version 5.0.

  5. Quality of Life and pain score [ Time Frame: Up to 1 year post-treatment ]
    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.

Other Outcome Measures:
  1. Estrogen receptor and progesterone receptor expression [ Time Frame: Up to 1 year post-treatment ]
    Assessed by immunohistochemistry and represented as a percentage prior to trial initiation and at progression.

  2. Percent change in Ki-67 [ Time Frame: Baseline up to 4 weeks ]
    Anti-proliferative effect is assessed by the percent change in Ki-67 after 4 weeks of randomization relative to baseline.

  3. Phosphorylated progesterone receptor and progesterone receptor target gene expressions [ Time Frame: Up to 1 year post-treatment ]
    Assessed by NanoString nCounter oncology panel system at baseline and at time of progression assessed as a percent

  4. Next generation sequencing changes [ Time Frame: Baseline up to 1 year post-treatment ]
    Next generation sequencing changes are assessed at baseline and at time of progression.

  5. Circulating tumor cells (CTCs) analysis [ Time Frame: Up to 1 year post-treatment ]
    CTCs will be assessed to examine the progesterone receptor at diagnosis and at progression.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts 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 front line therapy with carboplatin/paclitaxel
  • 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 >= 10 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
  • They cannot receive chemotherapy, immunotherapy or other endocrine therapy concurrently
  • 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
  • Postmenopausal females are only eligible for this study. This is defined as being status post (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
  • 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
  • Patients with concurrent second malignancy (other than non-melanoma skin cancer or curatively treated in situ carcinoma)
  • 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
  • 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
  • Participants must have recovered from all adverse events (AEs) due to previous therapies to =< grade 1 or baseline. Participants with =< grade 2 neuropathy may be eligible
  • 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 moderate severity or worse
  • Women who are pregnant or nursing
  • Women who are pre-menopausal
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04719273

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Contact: Russell Schilder, MD 215-955-8874

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United States, Pennsylvania
Thomas Jefferson University Recruiting
Philadelphia, Pennsylvania, United States, 19107
Contact: Russell Schilder, MD    215-955-8874   
Jefferson Health - Asplundh Cancer Pavilion Recruiting
Willow Grove, Pennsylvania, United States, 19090
Contact: Russell Schilder, MD    215-955-8874   
Sponsors and Collaborators
Thomas Jefferson University
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Responsible Party: Thomas Jefferson University Identifier: NCT04719273    
Other Study ID Numbers: 20P.829
First Posted: January 22, 2021    Key Record Dates
Last Update Posted: June 4, 2021
Last Verified: June 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Endometrial Neoplasms
Cystadenocarcinoma, Serous
Carcinoma, Endometrioid
Adenocarcinoma, Clear Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Uterine Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms by Site
Uterine Diseases
Neoplasms, Cystic, Mucinous, and Serous
Ovarian Neoplasms
Ovarian Diseases
Adnexal Diseases
Gonadal Disorders
Endocrine System Diseases
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists