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
Brief Summary
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.
Study Phase
Phase 2
Study Type
Interventional
Primary Outcome
Objective response rate (ORR)
Secondary Outcome
Disease Control Rate
Condition
Endometrial Cancer
Intervention
Onapristone, Extended-Release Formulation
Study Arms / Comparison Groups
Single Arm
Description: 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.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
25
Start Date
January 28, 2021
Completion Date
December 15, 2023
Primary Completion Date
December 15, 2022
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.
Gender
Female
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
, 215-955-8874, [email protected]
Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT04719273
Organization ID
20P.829
Responsible Party
Sponsor
Study Sponsor
Thomas Jefferson University
Study Sponsor
, ,
Verification Date
February 2021