Ignite Creation Date:
2024-05-06 @ 2:45 PM
Last Modification Date:
2024-10-26 @ 1:37 PM
Study NCT ID:
NCT04418089
Status:
COMPLETED
Last Update Posted:
2020-06-05
First Post:
2020-05-27
Brief Title:
Simvastatin Effect in Combination With Neoadjuvant Chemotherapy to Clinical Response and Tumor-Free Margin in Locally Advanced Breast Cancer
Sponsor:
Indonesia University
Organization:
Indonesia University
Study Overview
Official Title:
Combination of CAF and Simvastatin Improves Response to Neoadjuvant Chemotherapy and Increases Tumor-Free Margin in Locally Advanced Breast Cancer A Randomized Double-Blind Placebo-Controlled Trial
Status:
COMPLETED
Status Verified Date:
2020-06
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:
None
Brief Summary:
Introduction Neoadjuvant chemotherapy NACT has been the standard therapy for treating patients with locally advanced breast cancer LABC Doxorubicin-based regimen showed a clinical response for 70-80 However the cardiotoxicity from it was not tolerable Simvastatin acts synergistically with doxorubicin against MCF-7 cells through downregulation of the cell cycle or induction of apoptosis Also it alleviates doxorubicin cardiotoxicity by attenuating ER stress and activating the Akt pathway Hmgcris a new pathway mediating doxorubicin-induced cell death and cholesterol control drugs combined with doxorubicin could enhance efficacy and reduce side effects This study is conducted to see the combination simvastatin and CAF would increase the NACT response and surgical margin of LABC patients
Methods This study was a double-blind randomized placebo-controlled trial conducted in dr Cipto Mangunkusumo General Hospital and Koja General Hospital A total of 70 LABC patients were assessed for eligibility Patients received either a combination of CAF-Simvastatin 40 mgday or CAF-Placebo The biopsy was taken pre-NACT to make the histopathological diagnosis and examine the expression of HMG-CoA Reductase Hmgcr and P-glycoprotein P-gp Patients were evaluated for the clinical response after 3 cycles If the response was positive patients will proceed to surgery Then the post-operative specimen will be reviewed for the pathological response However if it was a negative response patients will be given 2nd line NACT
Methods This study was a double-blind randomized placebo-controlled trial conducted in dr Cipto Mangunkusumo General Hospital and Koja General Hospital A total of 70 LABC patients were assessed for eligibility Patients received either a combination of CAF-Simvastatin 40 mgday or CAF-Placebo The biopsy was taken pre-NACT to make the histopathological diagnosis and examine the expression of HMG-CoA Reductase Hmgcr and P-glycoprotein P-gp Patients were evaluated for the clinical response after 3 cycles If the response was positive patients will proceed to surgery Then the post-operative specimen will be reviewed for the pathological response However if it was a negative response patients will be given 2nd line NACT
Detailed Description:
Backgrounds Neoadjuvant chemotherapy NACT which is followed by surgery is now a standard therapy in the local advanced breast cancer LABC since it was introduced 50 years ago increasingly being used in early-stage LABC patients Some NACT studies in RSCM use a doxorubicin-based regimen giving a 70-80 partial response but do not require a complete response both clinically and pathologically The NACT response was 80 with a complete clinical response of 36 The complete pathological response obtained after NACT is the prognosis of a replacement marker both overall and disease-free survival in the LABC The purpose of giving NACTis to increase tumor resectability and de-escalation surgery and kill micrometastasis which will increase the length of disease-free and life expectancy of the patient New tumor margins causing post-NACT tumor shrinkage can be used as surgical margins
Doxorubicin-based chemotherapy is the most commonly given chemotherapy for NACT as well as entering the first line of the National Formulary However side effects are limited from drug resistance side effects that can cause cardiomyopathy and heart failure One of the factors that influence doxorubicin resistance is the presence of efflux pumps such as P-glycoprotein P-gp on the cell surface While the effects of toxicity arise due to the formation of reactive oxygen species ROS and the presence of free radicals Efforts to improve the efficacy of the combination of chemotherapy currently being used with targeted therapies such as anti-HER-2 and bevacizumab but have a high enough toxicity and are expensive and not included in ForNas Likewise some drugs that have been tested in vitro as P-gp inhibitorsmodifiers but failed in clinical trials because of ineffectiveness and greater side effects on the kidneys and heart Some previous studies have confirmed that simvastatin is a potential ABCB1 P-gp inhibitor
Statins are the most widely used anti-hypercholesterolemia in the world through inhibition of 3-hydroxy-3-methylglutaryl coenzyme-A reductase Hmgcr which is an enzyme that limits the use of the mevalonate pathway that can be used as intracellular cholesterol Besides having pleiotropic effects statins also have anti-tumor effects At this time statins have received approval as a potential anti-tumor agent because several epidemiological studies have agreed on the relationship between statin use and reducing the risk of recurrence of LABC after adjuvant therapy Some preclinical studies show that statins can decrease breast cancer cell proliferation and induce apoptosis in various experimental models results from pre-operative window-of-opportunity clinical trials on LABC so that statins can reduce tumor proliferation and induce apoptosis Reports in the RSCM get simvastatin 40 mg for 4 weeks for neoadjuvant reduce the proliferation index in the LABC by 533 and inhibit the increase in LABC cells through the Rho Rock pathway Although several studios of statin antitumor activity have been carried out the role of statins in oncology has not yielded satisfactory results or controversies and provides heterogeneous responses depending on the molecular identity and tumor type malignancy The results of a clinical preliminary study indicate that giving a single statin is not as effective as an anti-cancer because it requires large effects and large side effects
Several in vitro studies and animal models show that the combination of statins can increase the accumulation of intra-cell chemotherapy so that the effects of potentiation of chemotherapy arise The administration of a combination of doxorubicin statins increases the potential for anti-cancer effects through the accumulation of doxorubicin in cancer cells causing the potential for DNA damage inhibition of proliferation and induction of apoptosis statins can also protect cardiotoxic induced by doxorubicin if it is given pre-therapy in mice With a variety of anti-tumor mechanisms as well as the enormous benefits and potential addition of statins that can be well-tolerated safe and inexpensive However until now the effects of antiproliferation synergy and induction of apoptosis combination of simvastatin and doxorubicin in LABC patients are not well known This study aims to determine the efficacy tolerability and safety of simvastatin combination and CAF chemotherapy as neo-advanced therapy in LABC patients The use of this combination is expected to improve clinical and pathological responses as well as surgical margins while providing cardioprotection effects so as to provide the best service with high oncological value
Methods
1 Subject and study design This research is a double-blind placebo-controlled clinical trial conducted at Dr Cipto Mangunkusumo General Hospital and Koja General Hospital from January 2018 to September 2019 Eligible patients are patients with grade IIIA to IIIC invasive breast cancer that is histologically proven A total of 60 LABC patients were included in this study Participants received a combination of NACT CAF and Simvastatin 40 mg day n 30 or placebo n 30 Besides being used to make a histopathological diagnosis samples were taken by biopsy before NACT examined for the expression of HMG-CoA Reductase HMGCR and P-glycoprotein P-gp Participants were evaluated for the clinical response after 3 NACT cycles If it gives a complete or partial response then the patient will proceed to surgery Then the postoperative specimen will be reviewed for a pathological response However if it is stable or progressive the patient will be given a 2nd line NACT
2 Tumor assessment The primary outcome was clinical response while the secondary outcome was the pathological response incision boundary P-gp expression Hmgcr expression and side effects The analysis was performed on the population per protocol Clinical response assessment uses WHO 1979 criteria Pathological responses of tumors are evaluated according to the Miller-Payne scoring system MPG classification is used to evaluate the relevance between pathological response and clinical response The incision boundary assessment is performed using histopathological tissue incisions depending on the surgical margins of the tumor on the medial lateral cranial caudal and baseline sides of the tumor based on the size of the new tumor Histopathological results will determine whether the level is free from the tumor or not based on the size of the new tumor Disease assessment is carried out by investigation after 3 NACT cycles Side effects were assessed during treatment and for 7 days after the last treatment dose and assessed using CTCAE 30
3 Biomarker assessment Estimation of P-glycoprotein Pgp and Hmgcr expression was seen under a microscope from a sample after a core biopsy was performed before starting chemotherapy P-gp expression was interpreted based on the percentage of p-glycoprotein positive cells in the total cell population low 0 1 1-19 and 2 20-100 positive cells Hmgcr expression is interpreted based on the percentage of Hmgcr positive cells in the total cell population negative 0 1 1-10 2 11-50 3 51-100 positive cells
4 Statistical analysis The main results in this study were clinical responses based on WHO 1970 criteria ORR values in this study were calculated from the ratio of the number of patients who showed a response complete and partial to the total number of patients and were analyzed using the Pearson Chi-Square Test Secondary outcomes in the form of pathological responses based on GMP and incision boundaries were analyzed using Fishers Exact Test Bivariate analysis of clinicopathological variables and molecular biology with the therapeutic response using the Continuity Correction Test and the Fischers Exact Test The results of the bivariate analysis with p 025 were performed multivariate analysis using the Logistic Regression Test The analysis was performed with the help of a computer using the SPSS 23 program Differences were stated to be meaningful and obtained p values 005
Doxorubicin-based chemotherapy is the most commonly given chemotherapy for NACT as well as entering the first line of the National Formulary However side effects are limited from drug resistance side effects that can cause cardiomyopathy and heart failure One of the factors that influence doxorubicin resistance is the presence of efflux pumps such as P-glycoprotein P-gp on the cell surface While the effects of toxicity arise due to the formation of reactive oxygen species ROS and the presence of free radicals Efforts to improve the efficacy of the combination of chemotherapy currently being used with targeted therapies such as anti-HER-2 and bevacizumab but have a high enough toxicity and are expensive and not included in ForNas Likewise some drugs that have been tested in vitro as P-gp inhibitorsmodifiers but failed in clinical trials because of ineffectiveness and greater side effects on the kidneys and heart Some previous studies have confirmed that simvastatin is a potential ABCB1 P-gp inhibitor
Statins are the most widely used anti-hypercholesterolemia in the world through inhibition of 3-hydroxy-3-methylglutaryl coenzyme-A reductase Hmgcr which is an enzyme that limits the use of the mevalonate pathway that can be used as intracellular cholesterol Besides having pleiotropic effects statins also have anti-tumor effects At this time statins have received approval as a potential anti-tumor agent because several epidemiological studies have agreed on the relationship between statin use and reducing the risk of recurrence of LABC after adjuvant therapy Some preclinical studies show that statins can decrease breast cancer cell proliferation and induce apoptosis in various experimental models results from pre-operative window-of-opportunity clinical trials on LABC so that statins can reduce tumor proliferation and induce apoptosis Reports in the RSCM get simvastatin 40 mg for 4 weeks for neoadjuvant reduce the proliferation index in the LABC by 533 and inhibit the increase in LABC cells through the Rho Rock pathway Although several studios of statin antitumor activity have been carried out the role of statins in oncology has not yielded satisfactory results or controversies and provides heterogeneous responses depending on the molecular identity and tumor type malignancy The results of a clinical preliminary study indicate that giving a single statin is not as effective as an anti-cancer because it requires large effects and large side effects
Several in vitro studies and animal models show that the combination of statins can increase the accumulation of intra-cell chemotherapy so that the effects of potentiation of chemotherapy arise The administration of a combination of doxorubicin statins increases the potential for anti-cancer effects through the accumulation of doxorubicin in cancer cells causing the potential for DNA damage inhibition of proliferation and induction of apoptosis statins can also protect cardiotoxic induced by doxorubicin if it is given pre-therapy in mice With a variety of anti-tumor mechanisms as well as the enormous benefits and potential addition of statins that can be well-tolerated safe and inexpensive However until now the effects of antiproliferation synergy and induction of apoptosis combination of simvastatin and doxorubicin in LABC patients are not well known This study aims to determine the efficacy tolerability and safety of simvastatin combination and CAF chemotherapy as neo-advanced therapy in LABC patients The use of this combination is expected to improve clinical and pathological responses as well as surgical margins while providing cardioprotection effects so as to provide the best service with high oncological value
Methods
1 Subject and study design This research is a double-blind placebo-controlled clinical trial conducted at Dr Cipto Mangunkusumo General Hospital and Koja General Hospital from January 2018 to September 2019 Eligible patients are patients with grade IIIA to IIIC invasive breast cancer that is histologically proven A total of 60 LABC patients were included in this study Participants received a combination of NACT CAF and Simvastatin 40 mg day n 30 or placebo n 30 Besides being used to make a histopathological diagnosis samples were taken by biopsy before NACT examined for the expression of HMG-CoA Reductase HMGCR and P-glycoprotein P-gp Participants were evaluated for the clinical response after 3 NACT cycles If it gives a complete or partial response then the patient will proceed to surgery Then the postoperative specimen will be reviewed for a pathological response However if it is stable or progressive the patient will be given a 2nd line NACT
2 Tumor assessment The primary outcome was clinical response while the secondary outcome was the pathological response incision boundary P-gp expression Hmgcr expression and side effects The analysis was performed on the population per protocol Clinical response assessment uses WHO 1979 criteria Pathological responses of tumors are evaluated according to the Miller-Payne scoring system MPG classification is used to evaluate the relevance between pathological response and clinical response The incision boundary assessment is performed using histopathological tissue incisions depending on the surgical margins of the tumor on the medial lateral cranial caudal and baseline sides of the tumor based on the size of the new tumor Histopathological results will determine whether the level is free from the tumor or not based on the size of the new tumor Disease assessment is carried out by investigation after 3 NACT cycles Side effects were assessed during treatment and for 7 days after the last treatment dose and assessed using CTCAE 30
3 Biomarker assessment Estimation of P-glycoprotein Pgp and Hmgcr expression was seen under a microscope from a sample after a core biopsy was performed before starting chemotherapy P-gp expression was interpreted based on the percentage of p-glycoprotein positive cells in the total cell population low 0 1 1-19 and 2 20-100 positive cells Hmgcr expression is interpreted based on the percentage of Hmgcr positive cells in the total cell population negative 0 1 1-10 2 11-50 3 51-100 positive cells
4 Statistical analysis The main results in this study were clinical responses based on WHO 1970 criteria ORR values in this study were calculated from the ratio of the number of patients who showed a response complete and partial to the total number of patients and were analyzed using the Pearson Chi-Square Test Secondary outcomes in the form of pathological responses based on GMP and incision boundaries were analyzed using Fishers Exact Test Bivariate analysis of clinicopathological variables and molecular biology with the therapeutic response using the Continuity Correction Test and the Fischers Exact Test The results of the bivariate analysis with p 025 were performed multivariate analysis using the Logistic Regression Test The analysis was performed with the help of a computer using the SPSS 23 program Differences were stated to be meaningful and obtained p values 005
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None