Ignite Creation Date:
2024-05-06 @ 8:02 AM
Last Modification Date:
2024-10-26 @ 11:55 AM
Study NCT ID:
NCT02651844
Status:
COMPLETED
Last Update Posted:
2022-05-06
First Post:
2016-01-04
Brief Title:
Mifepristone for Breast Cancer Patients With Higher Levels of Progesterone Receptor Isoform A Than Isoform B
Sponsor:
Hospital Provincial Magdalena V de Martínez
Organization:
Hospital Provincial Magdalena V de Martínez
Study Overview
Official Title:
Mifepristone Treatment for Breast Cancer Patients Expressing Levels of Progesterone Receptor Isoform A PRA Higher Than Those of Isoform B PRB Neoadjuvant Therapy
Status:
COMPLETED
Status Verified Date:
2020-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
MIPRA
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 andor an increase in apoptotic markers
Eligibility
Postmenopausal women one year after menses stop
Women with tumors showing ratios of PRAPRB higher than 15 and PR higher than 50
Women without previous treatment
All clinical stages with tumors larger than 15 cm
Patients without autoimmune diseases andor asthma
Study design
Open Interventional
Twenty women will take MFP 200 mg po 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
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 andor an increase in apoptotic markers
Eligibility
Postmenopausal women one year after menses stop
Women with tumors showing ratios of PRAPRB higher than 15 and PR higher than 50
Women without previous treatment
All clinical stages with tumors larger than 15 cm
Patients without autoimmune diseases andor asthma
Study design
Open Interventional
Twenty women will take MFP 200 mg po 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 15 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 mgday As an antiglucocorticoid it has potential use in different psychiatric disorders including depression and Alzheimers 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 mgday 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 ClinicalTrialsgov 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 PRAPRB 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 microRNAstumor 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 po 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 helppharmawebcanadacom 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 AuthoritiesThe 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 -80C for genomicproteomic 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 SA 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 PRAPRB ratio Procedures will be recorded Results will be sent to DrLiguori 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 administrationcompliance 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 005 and Type 2 010 Power 08 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 373 of patients have PRAPRB higher than 15 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 clinicaltrialsgov
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
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 15 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 mgday As an antiglucocorticoid it has potential use in different psychiatric disorders including depression and Alzheimers 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 mgday 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 ClinicalTrialsgov 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 PRAPRB 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 microRNAstumor 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 po 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 helppharmawebcanadacom 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 AuthoritiesThe 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 -80C for genomicproteomic 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 SA 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 PRAPRB ratio Procedures will be recorded Results will be sent to DrLiguori 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 administrationcompliance 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 005 and Type 2 010 Power 08 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 373 of patients have PRAPRB higher than 15 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 clinicaltrialsgov
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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None