A Randomized Controlled Trial of Neoadjuvant Weekly Paclitaxel Versus Weekly Paclitaxel Plus Weekly Carboplatin In Women With Large Operable or Locally Advanced, Triple Negative Breast Cancer (TNBC)

November 20, 2023 updated by: Dr Rajendra A. Badwe, Tata Memorial Hospital

Triple-negative breast cancer is a subtype of breast cancer that is clinically negative for expression of estrogen and progesterone receptors (ER/PR) and HER2 protein. It is characterized by its unique molecular profile, aggressive behavior, distinct patterns of metastasis, and lack of targeted therapies. Although not synonymous, the majority of triple-negative breast cancers carry the "basal-like" molecular profile on gene expression arrays.

Although sensitive to chemotherapy, early relapse is common and these cancers show a predilection for visceral metastasis, including brain metastasis. Targeted agents, including epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and poly (ADP-ribose) polymerase (PARP) inhibitors, are currently in clinical trials and hold promise in the treatment of this aggressive disease.

Multiple independent data sets have revealed that the triple negative type of breast cancer carries a poor prognosis. It is unclear whether the poor prognosis of triple negative breast cancer is due to poor therapy options or inherent aggressiveness. Given their triple negative receptor status, these tumors are not amenable to conventional targeted therapies for breast cancer, such as endocrine therapy or trastuzumab, leaving only chemotherapy in the therapeutic armamentarium.

Patients on metformin showed a 30-40% protection against all forms of cancer. Recent pilot studies carried out using population registries raise the possibility that metformin may reduce cancer risk and/or improve cancer prognosis. One showed an unexpectedly lower risk of a cancer diagnosis among diabetics using metformin compared with a control group of diabetics using other treatments ; another showed lower cancer-specific mortality among subjects with diabetes using metformin compared with diabetics on other treatments. Metformin is a biguanide known to be an insulin sensitizing agent which promotes reduced circulating insulin and glucose levels in hyper-glycaemic and hyper-insulinaemic patients. Metformin activates the AMP dependent kinase, attenuates insulin and IGF-1 stimulated proliferation in breast cancer cells and a general decrease in protein synthesis in vitro. Western blot analysis indicated that metformin stimulates AMPK phosphorylation in a dose-dependent manner. AMPK activation is associated with decreased phosphorylation of mTOR and S6 kinase. While metformin reduces breast carcinoma cell proliferation both in vitro and in vivo, the activation of AMPK leads to significant VEGF production, angiogenesis and tumor progression. This must be taken into consideration when it is applied in as a therapeutic regimen.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

720

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • India
    • Maharashtra
      • Mumbai, Maharashtra, India, 400012
        • Tata Memorial Centre

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 70 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Age 18-70 years
  2. All patients with baseline clinical staging T4, N0-3, M0 or T1-4, N2-3, M0 and T3, N1, M0 with triple negative hormone status.
  3. Patients with adequate baseline marrow function defined as ANC > 1500/mm3 and Platelet count > 1, 00,000/mm3.
  4. Patients with acceptable liver function tests (normal bilirubin and AST/ALT < 2 times the upper limit of normal) and normal renal function tests at baseline
  5. Patients willing to provide informed consent
  6. Patients fit for chemotherapy

Exclusion Criteria:

  1. Prior excision biopsy
  2. Metastatic breast cancer
  3. Women with inflammatory breast cancer
  4. Poor cardiac function at baseline with LVEF <40%
  5. Patients with a prior history of a malignancy
  6. Pregnant or lactating women.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: A
weekly Paclitaxel chemotherapy at the dose of 100 mg/m2/week for 8 weeks as a 1-hour infusion and AC/EC (60/600 or 90/600) / 3 weekly.
Drug: Paclitaxel only
Experimental: B
weekly Paclitaxel at 100mg /m2/week + weekly Carboplatin AUC-2 as an infusion over 60 minutes and AC/EC (60/600 or 90/600)/ 3 weekly.
Drug: Paclitaxel + Carboplatin
Platinum based chemotherapy against the standard taxane based chemotherapy in the neo- adjuvant setting

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
DFS
Time Frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months
Disease free survival
From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months
OS
Time Frame: From date of randomization to the date of death or up to date of last follow-up for alive patients whichever came first, assessed up to 60 months
Overall survival
From date of randomization to the date of death or up to date of last follow-up for alive patients whichever came first, assessed up to 60 months

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Response rate
Time Frame: 9-12 months from Randomization
Clinical response evaluation during and at the end of Neo-adjuvant Chemotherapy
9-12 months from Randomization

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Tata Memorial Hospital

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

April 1, 2010

Primary Completion (Estimated)

November 30, 2025

Study Completion (Estimated)

November 30, 2025

Study Registration Dates

First Submitted

May 20, 2017

First Submitted That Met QC Criteria

May 25, 2017

First Posted (Actual)

May 30, 2017

Study Record Updates

Last Update Posted (Actual)

November 22, 2023

Last Update Submitted That Met QC Criteria

November 20, 2023

Last Verified

November 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CTRI/2012/07/002802

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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