Simvastatin Effect in Combination With Neoadjuvant Chemotherapy to Clinical Response and Tumor-Free Margin in Locally Advanced Breast Cancer

NCT04418089 | Completed Phase 2 DMC

• 1 other identifier: 18040334
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

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.

Conditions

Breast Cancer; Chemotherapy Effect

Keywords

Simvastatin; Local Advanced Breast Cancer; Clinical Response; Pathological Response; Surgical Margins; Neoadjuvant Chemoterapy

Outcome Measures

Primary Outcomes (1)

• Clinical Response as WHO 1979

  Clinical Response is measured using WHO 1979 criteria. 1. Complete Response (CR): Disappearance; confirmed at 3 months 2. Partial Response (PR): 50% decrease; confirmed at 3 months 3. Stable Disease(SD): Neither PR nor PD criteria met 4. Progressive Disease (PD):25% increase; no CR, PR, or SD documented before increased disease

  3 months

Secondary Outcomes (4)

• Pathological Response as Measured by Miller-Payne system

  3 months

• Surgical margin as measured by histopathological

  3 months

• Association of P-gp expression with response by WHO criteria

  3 months

• Association of Hmgcr expression with response by WHO criteria

  3 months

Study Arms (2)

Simvastatin

EXPERIMENTAL

The group received standard treatment with the oral administration of Simvastatin

Drug: Simvastatin 40mg

Placebo

EXPERIMENTAL

The group received standard treatment with the oral administration of Placebo

Drug: Placebo oral capsule

Interventions

Simvastatin 40mg DRUG

The administration of Simvastatin 40 mg in addition to neoadjuvant chemoterapy CAF

Simvastatin

Placebo oral capsule DRUG

The administration of Placebo capsule 40 mg in addition to neoadjuvant chemoterapy CAF

Placebo

Eligibility Criteria

• Sex: female
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• LABC patients are both residual and recurrent.
• Allergy to tattoo ink
• Allergy to statins
• Patients are pregnant or breastfeeding

Sponsors & Collaborators

• Indonesia University: lead

Study Sites (1)

Faculty of Medicine, Universitas Indonesia

Jakarta Pusat, DKI Jakarta, 10430, Indonesia

Location

MeSH Terms

Conditions

Breast Neoplasms; Margins of Excision

Interventions

Simvastatin

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Morphological and Microscopic Findings; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Lovastatin; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds

Study Officials

• Nurjati Chairani Siregar, MD

  Department of Pathology, Dr. Cipto Mangunkusumo General Hospital, Jakarta, Indonesia

  STUDY CHAIR

• Baju Adji

  Department of Surgery, Koja General Hospital, Jakarta, Indonesia

  STUDY CHAIR

• Filipus Dasawala, MD

  Department of Surgery, Dr. Cipto Mangunkusumo General Hospital, Jakarta, Indonesia

  STUDY CHAIR

• Hanifah Hasan, MD

  Internship Program as Research Assistant, Department of Surgery, Dr. Cipto Mangunkusumo General Hospital, Jakarta, Indonesia

  STUDY CHAIR

• Muhammad Rizki Kamil, MD

  Internship Program as Research Assistant, Department of Surgery, Dr. Cipto Mangunkusumo General Hospital, Jakarta, Indonesia

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: SUPPORTIVE CARE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Lecturer, Staff of Oncology Division of Department of Surgery, Principal Investigator

Study Record Dates

• First Submitted: May 27, 2020
• First Posted: June 5, 2020
• Study Start: January 15, 2018
• Primary Completion: May 20, 2019
• Study Completion: September 5, 2019
• Last Updated: June 5, 2020

Record last verified: 2020-06

Data Sharing

• IPD Sharing: Will not share

Locations

ID (1)