Neoadjuvant Chemotherapy With or Without GnRH Agonist for Premenopausal Triple-negative Early Breast Cancer Patients (ESCALATE)

January 28, 2024 updated by: National Taiwan University Hospital

A Randomized Phase II Study of Neoadjuvant Chemotherapy With or Without GnRH Agonist for Premenopausal Triple-negative Early Breast Cancer Patients: ESCALATE Study

Breast cancer (BC), especially premenopausal, is emerging rapidly in East Asia in recent 20 years. Half of the breast cancer patients in Asia are younger than 50 years of age. In general, younger or premenopausal patients are associated with poorer prognosis.

Premenopausal patients have higher estrogen levels than those in older (postmenopausal) patients. Estrogen is known to suppress anti-tumor T cell response and leading to tumor progression in different animal models (Clin Cancer Res 2016 22:6204), including lung cancer, melanoma, ovarian cancer. One of the mechanisms that contributes to estrogen's suppression of T cell function is via the mobilization of myeloid-derived suppressor cells (MDSC). Targeting ER signaling with hormonal therapy can abolish MDSC mobilization, and sensitize tumor cells to antigen specific T cell or NK cell killing (Cancer Discovery 2018 7:72 2017). These study results further support the hypothesis that, E2 is associated with immunosuppressive effect, and may contribute to the suppression of immune surveillance in young female breast cancer patients. These results suggest that E2 may suppress anti-tumor immunity, and E2 reduction improve the anti-tumor immunity. In our preliminary works, the investigators found higher dose (equivalent to premenopausal women serum level) of E2 suppressed T cell activities, while lower dose E2 (postmenopausal serum level) activated T cell activity. The investigators have investigated the combination of anti-PD1 antibody and GnRH agonist plus exemestane (an aromatase inhibitor which will block the production of E2 from adipose tissue) in ER positive premenopausal breast cancer patient refractory to prior endocrine therapy in metastatic setting. The response rate was 38.4%, and median progression-free survival (PFS) was 10.2 months. This outstanding result were presented in AACR 2021 oral session (Cancer Res 2021 81:13_Supplement, CT028). On the other hand, progesterone is also well known for its anti-inflammation and immune tolerance activity. This possibly makes estrogen reduction treatments, such as gonadotropin-releasing hormone agonist (GnRH agonist), an important partner in augmenting neoadjuvant therapy for patients with premenopausal breast cancer.

For triple negative breast cancer (TNBC), endocrine therapy has no anti-tumor effect. On the other hand, the use of GnRH agonist has been tested for the protection of ovary function of young female while receiving adjuvant chemotherapy. Surprisingly, the concomitant use of goserelin and adjuvant chemotherapy improved disease-free survival (HR 0.47, P=0.04) and overall survival (HR 0.45, P=0.05) versus chemotherapy alone in ER negative premenopausal early BC patients in POEMS study, which was initially aimed to improve the success pregnant rate (N Engl J Med 2015 372;923). Endocrine therapy is theoretically antagonist to chemotherapy therapy when concomitantly use. In another report analyzed the outcome of both pre- and postmenopausal women who entered two randomized trials (Gruppo Oncologico Nord-Ovest-Mammella Intergruppo studies) on adjuvant chemotherapy and received either concomitant or sequential hormonal therapy. The result showed a decreasing trend (P = 0.015) in hazard ratio of death with increasing age was observed, indicating that concomitant therapy is more effective than sequential therapy in young patients (Annals of Oncology 2008;19(2):299-307). These results support the hypothesis that, E2 suppression/ER inhibition therapy may modulate immune microenvironment, thereby enhancing the chemotherapy induced immunogenic death effect.

The investigators hypothesized that, estrogen level reduction by ovarian function suppression can modulate immune microenvironment, thereby augmenting adjuvant chemotherapy efficacy, regardless of the estrogen receptor (ER) status of cancer cell. Therefore, the investigators plan to test this hypothesis in real clinical model, with standard clinical recommended treatment doses.

The study is designed to evaluate whether the GnRH agonist can provide the therapeutic benefit for premenopausal TNBC patients via modulating immune microenvironment. Premenopausal TNBC patients will receive GnRH agonist and neoadjuvant chemotherapy, and the efficacy and immune microenvironment change of co-administration arm will be measured and compared with chemotherapy alone control arm.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

124

Phase

  • Phase 2

Contacts and Locations

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

Study Contact

Study Contact Backup

  • Name: Yen-Shen Lu, Ph.D.
  • Phone Number: 267513 +886-2-23123456
  • Email: yslu@ntu.edu.tw

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

  • Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

Patients eligible for inclusion in this study have to fulfill all of the following criteria:

  1. Written informed consent must be obtained before any assessment is performed.
  2. Female patients aged ≥ 18 years at screening; Must be age<50 years old with premenopausal status according to serum E2, FSH level.
  3. Histological confirmed TNBC, as defined by the most recent ASCO/CAP guidelines.
  4. Have previously untreated locally advanced non-metastatic (M0) TNBC defined as the following combined primary tumor (T) and regional lymph node (N) staging per current AJCC staging criteria for breast cancer staging criteria as assessed by the investigator based on radiological and/or clinical assessment: T1c, N1-N2; or T2, N0-N2; or T3, N0-N2; or T4a-d, N0-N2.
  5. Agree to receive core needle biopsy for translational research.
  6. ECOG 0-1 .

  7. Patients must have adequate organ and marrow reserve measured within 14 days prior to randomization as defined below:

    • Hemoglobin ≥ 9.0 g/dL;;
    • Absolute neutrophil count ≥ 1,500 /μL;
    • Platelets ≥ 100,000/μL;
    • Total bilirubin ≤1.5 x upper normal limit;
    • AST(SGOT)/ALT(SGPT) ≤ 2.5 x upper normal limit;
    • Serum creatinine ≤ 1.5mg/dL or creatinine clearance ≧50ml/min;
    • aPTT < 1.5 x upper normal limit (unless on therapeutic anti-coagulation);
  8. Plan to receive breast cancer surgery.
  9. Have left ventricular ejection fraction (LVEF) of ≥50%.
  10. Must have a negative pregnancy test obtained within 3 days before starting therapy. Patients must not be breastfeeding.
  11. Patients must use effective contraception prior to study entry and for the duration of study participation, and for 6 months after the completion of therapy.
  12. Patients (or a surrogate) must be able to comply with study procedures and to give signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the clinical study protocol (CSP). The patients (or a surrogate) must be able to provide of signed and dated written ICF prior to any mandatory study specific procedures, sampling, and analyses.

Exclusion Criteria:

Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No additional exclusions may be applied by the Investigator, in order to ensure that the study population will be representative of all eligible patients.

  1. Patients have received any prior therapy (including surgery, radiotherapy, chemotherapy, immunotherapy, or hormone therapy) for breast cancer.
  2. Evidence of systemic metastasis.
  3. Pregnancy or lactation.
  4. Has a history of invasive malignancy ≤5 years prior to signing informed consent except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer.
  5. Has an active autoimmune disease that has required systemic treatment in past 2 years.
  6. Has a diagnosis of immunodeficiency or is receiving high dose of systemic steroid therapy. Patients with minor medical disease condition (i.e. mild asthma) requiring prednisolone equal to or less than 20 mg/day or the equivalent may be allowed.
  7. Has an active systemic bacterial, viral or fungal infection requiring systemic therapy.
  8. Psychiatric illness or social situation that would preclude study compliance.
  9. Serious non-healing wound, ulcer, or bone fracture. Except for breast cancer related non-healing wound or ulcer.
  10. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to enrolment.
  11. History of allergic reaction to compounds of similar chemical composition to the study drugs.

  12. Any of the following conditions or treatments that may impact the safety of the patient:

    • History of, or current, significant cardiac disease including cardiac failure (NYHA functional class II-IV), myocardial infarction (within 6 months), unstable angina (within 6 months), transient ischemic attack (within 6 months), stroke, cardiac arrhythmias requiring treatment or uncontrolled arterial hypertension.
    • Concomitant clinically significant cardiac arrhythmias, e.g., sustained ventricular tachycardia, and clinically significant second- or third-degree AV block without a pacemaker on screening electrocardiogram (ECG).
    • History of or active severe respiratory disease, including Chronic Obstructive Pulmonary Disease, interstitial lung disease or pulmonary fibrosis.
    • Severe hepatic impairment (Child-Pugh class C).
    • Any medically unstable condition as determined by the Investigator.
  13. Patients unable or unwilling to undergo serial breast tumor biopsy.
  14. History of hypersensitivity to any of the study drugs.

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
Experimental: Arm A

After randomization, patients in the experimental arm (Arm A) will receive GnRH agonist injection within 3 days of randomization and during neoadjuvant chemotherapy treatment. The protocol-defined chemotherapy will be given 7 to 14 days after GnRH agonist injection. The choice of GnRH agonist, including goserelin, leuprorelin and triptorelin giving in monthly, three-monthly or sixth-monthly, will be made by per investigator's discretion.

  • Anthracycline/cyclophosphamide combination or dose-dense schedule: anthracycline/cyclophosphamide combination (Use of dose-dense schedule or not will be stratified.)
  • Taxane (docetaxel or paclitaxel) ± optional platinum (Use of platinum or not will be stratified.)
Drug: Goserelin Acetate 3.6mg、Goserelin Acetate 10.8mg、Leuprolide Acetate 3.75mg、Leuprorelin Acetate 22.5mg、Triptorelin pamoate 11.25mg、Triptorelin pamoate 22.5mg
After randomization, patients in the experimental arm (Arm A) will receive GnRH agonist injection within 3 days of randomization and during neoadjuvant chemotherapy treatment. The choice of GnRH agonist, including goserelin, leuprorelin and triptorelin giving in monthly, three-monthly or sixth-monthly, will be made by per investigator's discretion.
No Intervention: Arm B
  • Anthracycline/cyclophosphamide combination or dose-dense schedule: anthracycline/cyclophosphamide combination (Use of dose-dense schedule or not will be stratified.)
  • Taxane (docetaxel or paclitaxel) ± optional platinum (Use of platinum or not will be stratified.)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Pathological complete response rate
Time Frame: During surgery
No invasive residual in breast or nodes; non-invasive breast residuals allowed
During surgery

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Event free survival
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
To compare the event-free survival (EFS) assessed by investigator in ITT population after neoadjuvant chemotherapy with/without ovary suppression
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
Quality of life from patient-report outcome
Time Frame: At Screening phase, at Treatment 1 cycle 3 day 1 ( each cycle is 14 days or 21 day) , at Treatment 2 cycle 1 day 1 ( each cycle is 21 days), at Treatment 2 cycle 4 day 1 ( each cycle is 21 days), through study completion, an average of 5 years
Quality of life will be assessed by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 , the minimum values is : 30 , the maximum values is : 126, the higher scores mean a worse outcome
At Screening phase, at Treatment 1 cycle 3 day 1 ( each cycle is 14 days or 21 day) , at Treatment 2 cycle 1 day 1 ( each cycle is 21 days), at Treatment 2 cycle 4 day 1 ( each cycle is 21 days), through study completion, an average of 5 years
Estradiol
Time Frame: At Screening phase, at Treatment 1 cycle 1 day 1, at Treatment 1 cycle 3 day 1, at Treatment 2 cycle 1 day 1, at Treatment 2 cycle 3 day 1, during surgery, through study completion, an average of 5 years
Estradiol (E2) pg/mL
At Screening phase, at Treatment 1 cycle 1 day 1, at Treatment 1 cycle 3 day 1, at Treatment 2 cycle 1 day 1, at Treatment 2 cycle 3 day 1, during surgery, through study completion, an average of 5 years
Follicle stimulating hormone
Time Frame: At Screening phase, at Treatment 1 cycle 1 day 1, at Treatment 1 cycle 3 day 1, at Treatment 2 cycle 1 day 1, at Treatment 2 cycle 3 day 1, during surgery, through study completion, an average of 5 years
Follicle stimulating hormone (FSH) mIU/mL
At Screening phase, at Treatment 1 cycle 1 day 1, at Treatment 1 cycle 3 day 1, at Treatment 2 cycle 1 day 1, at Treatment 2 cycle 3 day 1, during surgery, through study completion, an average of 5 years
Luteinizing hormone
Time Frame: At Screening phase, at Treatment 1 cycle 1 day 1, at Treatment 1 cycle 3 day 1, at Treatment 2 cycle 1 day 1, at Treatment 2 cycle 3 day 1, during surgery, through study completion, an average of 5 years
Luteinizing hormone (LH) mIU/mL
At Screening phase, at Treatment 1 cycle 1 day 1, at Treatment 1 cycle 3 day 1, at Treatment 2 cycle 1 day 1, at Treatment 2 cycle 3 day 1, during surgery, through study completion, an average of 5 years
Tumor microenvironment changes after neoadjuvant chemotherapy with/without ovarian suppression
Time Frame: At Screening phase, at Treatment 1 cycle 1 day 1 ( each cycle is 14 days or 21 days), at Treatment 2 cycle 1 day 1 ( each cycle is 21 days), through study completion, an average of 5 years
To evaluate the tumor-infiltrating lymphocytes (TIL)
At Screening phase, at Treatment 1 cycle 1 day 1 ( each cycle is 14 days or 21 days), at Treatment 2 cycle 1 day 1 ( each cycle is 21 days), through study completion, an average of 5 years
Pathological complete response by tumor infiltrating lymphocyte
Time Frame: During surgery
To evaluate the rate of pCR (ypT0/Tis ypN0) as assessed by the local pathologist at the time of definitive surgery in individuals with TIL(+) or TIL(-) tumors.
During surgery
Residual cancer burden
Time Frame: During surgery
To evaluate Residual Cancer Burden (RCB) as assessed by the local pathologist at the time of definitive surgery
During surgery
Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
Time Frame: up to 32 weeks
To determine the safety and tolerability of ovarian function suppression in combination with neoadjuvant chemotherapy in locally advanced TNBC subjects
up to 32 weeks
Breast cancer quality of life from patient-report outcome
Time Frame: At Screening phase, at Treatment 1 cycle 3 day 1 ( each cycle is 14 days or 21 day) , at Treatment 2 cycle 1 day 1 ( each cycle is 21 days), at Treatment 2 cycle 4 day 1 ( each cycle is 21 days), through study completion, an average of 5 years
Breast cancer quality of life will be assessed by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire BR23 , the minimum values is : 22 , the maximum values is : 92, the higher scores mean a worse outcome
At Screening phase, at Treatment 1 cycle 3 day 1 ( each cycle is 14 days or 21 day) , at Treatment 2 cycle 1 day 1 ( each cycle is 21 days), at Treatment 2 cycle 4 day 1 ( each cycle is 21 days), through study completion, an average of 5 years
Event free survival by tumor infiltrating lymphocyte
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.
To evaluate the event free survival by investigator in individuals with TIL(+) or TIL(-) tumors.
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.

Collaborators and Investigators

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

Sponsor

National Taiwan University Hospital

Collaborators

Debiopharm International SA
Ministry of Health and Welfare

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

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 (Estimated)

February 15, 2024

Primary Completion (Estimated)

December 1, 2026

Study Completion (Estimated)

December 1, 2030

Study Registration Dates

First Submitted

December 10, 2023

First Submitted That Met QC Criteria

January 17, 2024

First Posted (Actual)

January 25, 2024

Study Record Updates

Last Update Posted (Actual)

January 30, 2024

Last Update Submitted That Met QC Criteria

January 28, 2024

Last Verified

November 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 202309050MIPB

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

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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