Simvastatin Effect in Combination With Neoadjuvant Chemotherapy to Clinical Response and Tumor-Free Margin in Locally Advanced Breast Cancer
Primary Purpose
Breast Cancer, Chemotherapy Effect
Status
Completed
Phase
Phase 2
Locations
Indonesia
Study Type
Interventional
Intervention
Simvastatin 40mg
Placebo oral capsule
Sponsored by

About this trial
This is an interventional supportive care trial for Breast Cancer focused on measuring Simvastatin, Local Advanced Breast Cancer, Clinical Response, Pathological Response, Surgical Margins, Neoadjuvant Chemoterapy
Eligibility Criteria
Inclusion Criteria:
- LABC IIIA-IIIC TNM / AJCC 2018 with histopathological examination.
- Patients are planned to get NACT
- Performance status of Eastern Cooperative Oncology Group (ECOG) 0-2.
- LABC patients who have not received surgery, radiation or systemic therapy and previous statin therapy.
- Normal kidney organ function (serum creatinine ≤ 1.5 upper limit normal).
- Normal liver organ function (ALT ≤ 2 times the normal limit, or total bilirubin level ≤ 1.5 times the normal upper limit)
- Heart function (E / F)> 55%
- Willing to participate in this study by signing an informed consent
Exclusion Criteria:
- LABC patients are both residual and recurrent.
- Allergy to tattoo ink
- Allergy to statins
- Patients are pregnant or breastfeeding
Sites / Locations
- Faculty of Medicine, Universitas Indonesia
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Simvastatin
Placebo
Arm Description
The group received standard treatment with the oral administration of Simvastatin
The group received standard treatment with the oral administration of Placebo
Outcomes
Primary Outcome Measures
Clinical Response as WHO 1979
Clinical Response is measured using WHO 1979 criteria.
Complete Response (CR): Disappearance; confirmed at 3 months
Partial Response (PR): 50% decrease; confirmed at 3 months
Stable Disease(SD): Neither PR nor PD criteria met
Progressive Disease (PD):25% increase; no CR, PR, or SD documented before increased disease
Secondary Outcome Measures
Pathological Response as Measured by Miller-Payne system
Evaluation of the MP system is based on the reduction of tumor cellularity before and after chemotherapy, divided into:
Grade 1 ie there is no change or reduction in cancer cells.
Grade 2: reduction of <30% cancer cells
Grade 3: reduction of cancer cells between 30-90%
Grade 4: reduction of > 90% cancer cells
Grade 5 is that there are no residual cancer cells. Grade 4 is categorized as partial pathology response. Grade 5 is categorized as a complete pathology response
Surgical margin as measured by histopathological
histopathologically the tissue to the tumor incision limit on the medial, lateral, cranial, and caudal sides along with the tumor base; based on the size of the new tumor. Hisopathologically assesses the extent of incision free or not tumor based on the size of the new tumor.
Association of P-gp expression with response by WHO criteria
Clinical Response is measured using WHO 1979 criteria.
Complete Response (CR): Disappearance; confirmed at 3 months
Partial Response (PR): 50% decrease; confirmed at 3 months
Stable Disease(SD): Neither PR nor PD criteria met
Progressive Disease (PD):25% increase; no CR, PR, or SD documented before increased disease
Association of Hmgcr expression with response by WHO criteria
Clinical Response is measured using WHO 1979 criteria.
Complete Response (CR): Disappearance; confirmed at 3 months
Partial Response (PR): 50% decrease; confirmed at 3 months
Stable Disease(SD): Neither PR nor PD criteria met
Progressive Disease (PD):25% increase; no CR, PR, or SD documented before increased disease
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT04418089
Brief Title
Simvastatin Effect in Combination With Neoadjuvant Chemotherapy to Clinical Response and Tumor-Free Margin in Locally Advanced Breast Cancer
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
Study Type
Interventional
2. Study Status
Record Verification Date
June 2020
Overall Recruitment Status
Completed
Study Start Date
January 15, 2018 (Actual)
Primary Completion Date
May 20, 2019 (Actual)
Study Completion Date
September 5, 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Indonesia University
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes
5. Study Description
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 mg/day) 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 inhibitors/modifiers, 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 53.3% 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
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.
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 3.0.
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)..
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 Fisher's Exact Test. Bivariate analysis of clinicopathological variables and molecular biology with the therapeutic response using the Continuity Correction Test and the Fischer's Exact Test. The results of the bivariate analysis with p> 0.25 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 <0.05.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Breast Cancer, Chemotherapy Effect
Keywords
Simvastatin, Local Advanced Breast Cancer, Clinical Response, Pathological Response, Surgical Margins, Neoadjuvant Chemoterapy
7. Study Design
Primary Purpose
Supportive Care
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
60 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Simvastatin
Arm Type
Experimental
Arm Description
The group received standard treatment with the oral administration of Simvastatin
Arm Title
Placebo
Arm Type
Experimental
Arm Description
The group received standard treatment with the oral administration of Placebo
Intervention Type
Drug
Intervention Name(s)
Simvastatin 40mg
Intervention Description
The administration of Simvastatin 40 mg in addition to neoadjuvant chemoterapy CAF
Intervention Type
Drug
Intervention Name(s)
Placebo oral capsule
Intervention Description
The administration of Placebo capsule 40 mg in addition to neoadjuvant chemoterapy CAF
Primary Outcome Measure Information:
Title
Clinical Response as WHO 1979
Description
Clinical Response is measured using WHO 1979 criteria.
Complete Response (CR): Disappearance; confirmed at 3 months
Partial Response (PR): 50% decrease; confirmed at 3 months
Stable Disease(SD): Neither PR nor PD criteria met
Progressive Disease (PD):25% increase; no CR, PR, or SD documented before increased disease
Time Frame
3 months
Secondary Outcome Measure Information:
Title
Pathological Response as Measured by Miller-Payne system
Description
Evaluation of the MP system is based on the reduction of tumor cellularity before and after chemotherapy, divided into:
Grade 1 ie there is no change or reduction in cancer cells.
Grade 2: reduction of <30% cancer cells
Grade 3: reduction of cancer cells between 30-90%
Grade 4: reduction of > 90% cancer cells
Grade 5 is that there are no residual cancer cells. Grade 4 is categorized as partial pathology response. Grade 5 is categorized as a complete pathology response
Time Frame
3 months
Title
Surgical margin as measured by histopathological
Description
histopathologically the tissue to the tumor incision limit on the medial, lateral, cranial, and caudal sides along with the tumor base; based on the size of the new tumor. Hisopathologically assesses the extent of incision free or not tumor based on the size of the new tumor.
Time Frame
3 months
Title
Association of P-gp expression with response by WHO criteria
Description
Clinical Response is measured using WHO 1979 criteria.
Complete Response (CR): Disappearance; confirmed at 3 months
Partial Response (PR): 50% decrease; confirmed at 3 months
Stable Disease(SD): Neither PR nor PD criteria met
Progressive Disease (PD):25% increase; no CR, PR, or SD documented before increased disease
Time Frame
3 months
Title
Association of Hmgcr expression with response by WHO criteria
Description
Clinical Response is measured using WHO 1979 criteria.
Complete Response (CR): Disappearance; confirmed at 3 months
Partial Response (PR): 50% decrease; confirmed at 3 months
Stable Disease(SD): Neither PR nor PD criteria met
Progressive Disease (PD):25% increase; no CR, PR, or SD documented before increased disease
Time Frame
3 months
10. Eligibility
Sex
Female
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
LABC IIIA-IIIC TNM / AJCC 2018 with histopathological examination.
Patients are planned to get NACT
Performance status of Eastern Cooperative Oncology Group (ECOG) 0-2.
LABC patients who have not received surgery, radiation or systemic therapy and previous statin therapy.
Normal kidney organ function (serum creatinine ≤ 1.5 upper limit normal).
Normal liver organ function (ALT ≤ 2 times the normal limit, or total bilirubin level ≤ 1.5 times the normal upper limit)
Heart function (E / F)> 55%
Willing to participate in this study by signing an informed consent
Exclusion Criteria:
LABC patients are both residual and recurrent.
Allergy to tattoo ink
Allergy to statins
Patients are pregnant or breastfeeding
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nurjati Chairani Siregar, MD
Organizational Affiliation
Department of Pathology, Dr. Cipto Mangunkusumo General Hospital, Jakarta, Indonesia
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Baju Adji
Organizational Affiliation
Department of Surgery, Koja General Hospital, Jakarta, Indonesia
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Filipus Dasawala, MD
Organizational Affiliation
Department of Surgery, Dr. Cipto Mangunkusumo General Hospital, Jakarta, Indonesia
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Hanifah Hasan, MD
Organizational Affiliation
Internship Program as Research Assistant, Department of Surgery, Dr. Cipto Mangunkusumo General Hospital, Jakarta, Indonesia
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Muhammad Rizki Kamil, MD
Organizational Affiliation
Internship Program as Research Assistant, Department of Surgery, Dr. Cipto Mangunkusumo General Hospital, Jakarta, Indonesia
Official's Role
Study Chair
Facility Information:
Facility Name
Faculty of Medicine, Universitas Indonesia
City
Jakarta Pusat
State/Province
DKI Jakarta
ZIP/Postal Code
10430
Country
Indonesia
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Simvastatin Effect in Combination With Neoadjuvant Chemotherapy to Clinical Response and Tumor-Free Margin in Locally Advanced Breast Cancer
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