Mifepristone for Breast Cancer Patients With Higher Levels of Progesterone Receptor Isoform A Than Isoform B.

NCT ID: NCT02651844

Last Updated: 2022-05-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-04-30
• Study Completion Date: 2019-10-31

Brief Summary

• Seventy per cent of breast cancers express estrogen (ER) and progesterone receptors (PR) and respond to endocrine treatment.
• Actual therapy targets ER.
• There is enough evidence that progestins participate regulating breast cancer growth.
• Antiprogestins block cell proliferation and increase apoptosis in breast cancer models which express high levels of PRA.
• Antiprogestins have been used to treat breast cancer patients that failed to other treatments; benefits were seen in selected patients.
• Mifepristone (MFP) is currently used for medical abortion and for the treatment of Cushing disease.
• MFP might exert agonistic effects when PRB isoform is activated by cAMP. This makes mandatory the evaluation of the PR isoform ratio in breast cancer patients in which MFP is a therapeutic possibility.

Main Goal To evaluate if therapeutic doses of MFP exert beneficial effects on breast cancers expressing levels of PRA higher than those of PRB, evaluated as an inhibition in proliferation markers and/or an increase in apoptotic markers.

• Eligibility

• Postmenopausal women (one year after menses stop).
• Women with tumors showing ratios of PRA/PRB higher than 1.5 and PR higher than 50%.
• Women without previous treatment.
• All clinical stages with tumors larger than 1.5 cm.
• Patients without autoimmune diseases and/or asthma.
• Study design

• Open Interventional.
• Twenty women will take MFP (200 mg) p.o. once /day during 14 days. As for preliminary studies, to reach this number the investigators will have to evaluate 80-100 patients.
• Surgery is performed 14 days after treatment initiation, 24 hs after last dose.
• PR isoform ratio will be evaluated by western blots (WB) in one core biopsy. Additional cores will be used for diagnosis, immunohistochemistry (IHC) of PR, Ki-67 and other markers.
• At surgery samples will be frozen for molecular studies and fixed and processed for pathological evaluation.
• Wilcoxon signed rank test will be used to evaluate differences in biomarker expression between core biopsy and surgical samples of each patient.
• Blood will be collected before treatment initiation and prior to final surgery.
• Mammographic and echographic studies will be carried out before and after treatment.

Detailed Description

Hypothesis

PR are involved in breast cancer growth. The antiprogestin mifepristone (MFP) exerts antitumor effects in mammary carcinomas with high expression of PRA. The investigators hypothesize that breast cancers with higher levels of PRA than PRB will benefit from an antiprogestin therapy.

Precis

The aim of the study is to select 20 breast cancer patients, with primary tumors expressing PR (50% or higher) and 1.5 fold PRA as compared with PRB, for a neoadjuvant treatment with mifepristone (MFP) during 14 days in between biopsy core and surgery. There are no studies at the present time selecting breast cancer patients according to the prevailing PR isoform expressed. This is extremely important since antiprogestins might have no effect or even stimulate those over-expressing PRB.

Background

Breast cancer remains one of the main causes of death in women. Current endocrine treatments are aimed to target either estrogen receptors (ER) or to inhibit the synthesis of 17-β-estradiol (E2). Emerging evidence obtained from experimental studies, as well as from human epidemiology, point to an important role for progestins in breast cancer growth.

Both PR isoforms are transcribed from the same gene. PRB has 933 amino acids while PRA lacks the first 164 amino acids. They play different roles in vivo as demonstrated using knock out models.

MFP, a progesterone antagonist, may also act as an agonist in the presence of PRB. In this context, MFP-bound PR recruit coactivators rather than corepressors. MFP may also exert antiglucocorticoid effects. As an antiprogestin it has been used for different obstetric indications, such as uterine ripening and intrauterine fetal death, at doses higher than 200 mg/day. As an antiglucocorticoid it has potential use in different psychiatric disorders, including depression and Alzheimer's and recently, the FDA approved its use for the treatment of Cushing disease (300 mg daily).

Antiprogestins in breast cancer treatment

The first clinical trial to evaluate antiprogestin therapy in patients recruited 22 patients for a third-line study. Patients were treated with MFP, 200 mg/day, for 1-3 months. There was an 18% response rate following 3 months of therapy. The long-term tolerance was good. Three other studies were reviewed together with unpublished results from a fifth study . There are no other published clinical results for breast cancer treatment using MFP.

More recently, four clinical trials have been recently launched for the evaluation of antiprogestins. The ClinicalTrials.gov Identifier: NCT01138553, testing MFP in neoadjuvancy was discontinued because of difficulties in recruiting and the NCT00555919, Schering, testing lonaprisan, was stopped due to lack of expected clinical response. Two other studies are under way, NCT01800422 testing telapristone and NCT02052128 onapristone.

Antiprogestins in preclinical studies

Using murine mammary carcinomas expressing different PR isoforms, and experimental human breast cancer models manipulated to express different PR ratios, the investigators have demonstrated that only tumors with levels of PRA higher than those of PRB regress with antiprogestin treatment. Moreover, breast cancer samples with higher levels of PRA than PRB respond ex vivo to MFP treatment.

Study design

Registration: The investigators will recruit patients with mammographic and echographic studies that a) have been diagnosed with breast cancer clinically (to be confirmed in biopsy) and b) surgery has been recommended for the treatment of this cancer. Patients will be interviewed by Dr. Gass, and /or Dr. Liguori, or Dr. Paula Martínez-Vazquez, and consented into the study. The original IC will be kept in the CRF of the patient and a copy in the main study file.

Anonymization and generation of the unique patient identifier: Research samples will be anonymized with an identification code. Only Dr. Gass and Dr. Lanari will have access to the codes.

Biopsies: After having signed the IC and having evaluated that the patient is potentially a candidate for the clinical trial, the patient will be biopsied under echographic guide. Three needle cores will be obtained to a) make the final diagnosis, b) measure PRA/PRB isoform ratio by western blot (WB), c) measure ER and PR by immunohistochemistry (IHC) and store the paraffin block for biomarker staining and, d) perform tumor transcriptome. Biopsy core will be flash frozen at -80 °C for molecular studies and the others fixed in 10% buffered formaldehyde for diagnosis determination and PR IHC following routine hospital guidelines.

Blood: Will be collected the same day of biopsy (40 ml by standard hospital procedures) and stored to make different studies in addition to the routine approach: a) MFP measuring b) purify circulating DNA/ microRNAs/tumor cells. This procedure will be repeated the day of surgery.

Diagnosis: Seventy two hours after biopsy, the diagnosis, the PR WB, and the IHC PR value will be available. If the patient qualifies she is ready for the 14 days treatment. All studies will be recorded in the CRF.

Treatment: Generic tablets of MFP 200 mg p.o once a day during 14 days. MFP will be imported from the international pharmacies of Pharma web Canada. Expiration date is July 2018. All medications are manufactured in FDA approved facilities (help@pharmawebcanada.com). Three cases of 99 units each will be purchased. When a patient enters the protocol, 14 pills will be given to the personnel responsible of giving the patient the medicine at her home (requirement from the Argentine Authorities).The form will be signed by patient, worker and by Dr. Gass and the form kept on the patient CRF.

Clinic Control: One week after treatment initiation, patient will go back to the hospital for a clinic control. Note: Due to the extended period of recruitmment, new mifepristone pills were purchased with expiration date October 2019.

Contraindications:

• MFP hypersensitivity.
• Chronic renal failure.
• Asthma.

Side effects: Severe side effects are not expected. Mild effects may include: nausea, vomits, lethargy at low levels. Patients that quit the protocol will be treated as those inside the protocol.

Contraindicated therapies: If women are taking other medication, the attending physicians will evaluate possible interactions case by case. The patient will be excluded from the protocol if needed. The patients will be instructed to notify the attending physician should the necessity arises to be put under a medication different from that administered as part of the trial.

Before surgery: New mammogram and ecography to compare images before and after treatment (no differences expected).

Surgery: Under routine Hospital guidelines for all breast cancer patients. It will be performed on day 15 after treatment initiation. Tissue will be collected for immunohistochemical staining (formalin fixed) and kept frozen at -80°C for genomic/proteomic studies. Blood will also collected as mentioned before.

Technical Procedures

Sample transport: Anonymized frozen samples will be sent to IBYME for WB studies in dry ice using a special transport Enterprise (Transportes Ambientales S.A). At IBYME Security personnel will record the arrival and then transported to the LCH Lab.

PR WB: Nuclear extracts will be performed and processed as described previously. T47D cells will be used as a positive control. Paola Rojas will be in charge of the determination of the PRA/PRB ratio. Procedures will be recorded. Results will be sent to Dr.Liguori and Dr. Gass, and a copy of them will be kept in the CRF.

PR IHC: Five micron paraffin embedded core tissues will be processed for standard PR IHC assays using FDA approved antibodies and quantified as described previously. Two pathologists (Dr. Gonzalez and Dr. May, supervised by Dr. Molinolo) will quantify and score the IHC staining. The pathologists will inform the PR score to Dr. Liguori, 72 hs after biopsy who will include the record at the patient CRF.

Decision for patient inclusion: Dr Liguori will be responsible of collecting the WB info and the PR IHC info and Dr. Gass will have to agree that the patient might enter the protocol because she matches with all the inclusion criteria. A signed form will be included at the patient CRF.

Biomarker evaluation: All assays for primary and secondary endpoints will be analyzed after concluding with patient recruitment. Nuclear Ki-67 staining will be evaluated according to Goldhirsch et al., 2013, and other biomarkers will be evaluated at the end of the study comparing biopsy and surgery scores of all patients recruited. Cytoplasmic, nuclear and membrane stainings will also be considered for biomarkers other than hormone receptors and Ki-67. Tumors with Ki-67 scoring differences greater than 10% between the two pathologists will be reevaluated until complete agreement is obtained. For differences less than 10%, the average score will be considered. If a positive response is seen (30% change in biomarker expression between biopsy and surgery), the investigators will start with the molecular analysis of the samples using available genomic platforms.

Statistics: Descriptive statistics will be used to summarize subject baseline characteristics, treatment administration/compliance, etc. Data will also be displayed graphically, when appropriate. An accounting of all subjects enrolled will be summarized. The number of subjects discontinuing from the study and the reasons for discontinuation will be tabulated. Subjects who did not meet eligibility criteria will be described. Demographic and baseline characteristics such as subject age, sex, race, height, weight, ECOG performance status, malignancy history, and medical history will be summarized. Wilcoxon signed rank test will be used to compare changes in biomarker expression.

Number of patients to be included: To calculate the number of patients to be included, the investigators fixed Type 1 error: 0.05 and Type 2: 0.10, Power 0.8. It was assumed that no differences should be registered between biopsy and surgery in the Ki-67 or apoptotic indices in the absence of treatment and considered a 30% decrease in Ki-67 a positive result. Unpublished data suggest that 37.3% of patients have PRA/PRB higher than 1.5 indicating that around 80 biopsies will be studied by WB to meet the right number.

Insurance: Prudencia Seguros, # 00056924 hired by the Hospital

Documents to include in the regulatory File:

1. Argentina Health Ministry Regulation Res 1480 ANMAT

2. Last version of the protocol presented to the ANMAT (version 3; March 16 2015)

3. Versions approved by clinicaltrials.gov

4. Model of IC

5. Participants CV

6. IRBs approvals and amendments

7. ANMAT form accepting drug importation

8. All forms related to medication administration mentioned previously

9. Documents related to the certification of the IRBs

10. Protocols concerning WB and IHC including methods of equipment calibration

11. SOP related to all clinical practice

The entire file will be available for possible inspection by the Institutional IRB or MINCYT, CONICET or other authorities who may be concerned. Dr. Gass will be responsible for providing all the data requested by the evaluating committees.

Notes: Dr M. Liguori is no longer in charge of the patients since August 2018. Dr Hugo Gass is in charge of patient recruitment, biopsies and clinic evaluation. Dr. Marìa May and Dr. Pedro Gonzalez, pathologists, are no longer involved in the study. They were replaced by Eunice Spengler and Silvia Ines Vanzulli.

Conditions

Breast Cancer

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Mifepristone

Tablets of Mifepristone 200 mg p.o. once a day during 14 days between biopsy and surgery after confirming inclusion criteria

Group Type: EXPERIMENTAL

Mifepristone

Intervention Type: DRUG

At the time a patient enters the protocol, 14 pills will be given to the personnel responsible of giving the patient the medicine at her home (This was a special requirement from the Argentine Authorities).

Patients and personnel will sign the form each then she gets the medication and after that the signed form will be kept at the CRF file.

Interventions

Mifepristone

At the time a patient enters the protocol, 14 pills will be given to the personnel responsible of giving the patient the medicine at her home (This was a special requirement from the Argentine Authorities).

Patients and personnel will sign the form each then she gets the medication and after that the signed form will be kept at the CRF file.

Intervention Type: DRUG

Other Intervention Names

RU-486

Eligibility Criteria

Inclusion Criteria

1. Postmenopausal women (one year after menses stop)

2. Confirmed diagnosis of breast cancer

3. Tumors with higher expression PR > 50 % measured by IHC and PRA/RPB ratio equal or higher than 1.5 measured by WB

4. All clinical stages with tumor size greater than 1.5 cm to allow obtaining material from biopsy cores

5. OMS condition: 1 Adequate function of organs and systems

Hematopoietic parameters:

• Hemoglobin: 10 gr/mL
• Neutrophil counting: 1.500/mm3
• CD4 counting: 400/mm3
• Platelets counting: 100.000/mm3 Liver parameters
• Total albumin: 1.5 fold normal limit
• AST/ALT: 1.5 fold normal limit Renal
• Creatinine: 1.5 fold normal limit 6. Absence of other controlled disease 7. Patients willing to sign consent

Exclusion Criteria

1. Patients with no recommended surgery

2. Patients which have received any other treatment for this cancer

3. Patients expressing ER but expressing PRA/PRB levels lower than 1.5

4. Hepatitis infection (HBV o HCV)

5. HIV infection.

6. Cognitive alterations which limit the understanding of the protocol or compliance to the protocol

7. Prolonged QT/QTc basal interval

• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

National Agency for Scientific and Technological Promotion, Argentina

OTHER

Sponsor Role: collaborator

Instituto de Biología y Medicina Experimental (IBYME-CONICET)

UNKNOWN

Sponsor Role: collaborator

Hospital Provincial Magdalena V. de Martínez

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Claudia Lanari, PhD

Role: STUDY_DIRECTOR

IBYME-CONICET

Locations

HospitalPMVM

General Pacheco, Buenos Aires, Argentina

Countries

Argentina

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Other Identifiers

PIDC-2012-0084

Identifier Type: -

Identifier Source: org_study_id