Clinical trial NCT06225284: Neoadjuvant Chemotherapy With or Without GnRH Agonist for Premenopausal Triple-negative Early Breast Cancer Patients
Official title: A Randomized Phase II Study of Neoadjuvant Chemotherapy With or Without GnRH Agonist for Premenopausal Triple-negative Early Breast Cancer Patients: ESCALATE Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Triple Negative Breast Cancer
Premenopausal Breast Cancer
Keywords: Neoadjuvant chemotherapy
Triple negative breast cancer
Gonadotropin Releasing Hormone Agonist
Premenopausal Breast Cancer
Lead sponsor: National Taiwan University Hospital
Sponsor class: OTHER
Collaborators: name: Ministry of Health and Welfare
name: Debiopharm International SA
First posted: 2024-01-25
Enrollment: 124
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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 premenopausal according to serum E2, FSH level.
3. Histological confirmed TNBC, as defined by the most recent ASCO/CAP guidelines. Hormone receptor-low/HER2 negative as defined by ER 1% to \<10% and/or PR 1% to \<10% on IHC staining; neither hormone receptor may be ≥ 10%; and HER2-negative (IHC 0+/1+, or IHC 2+ plus FISH negative) is allowed.
4. Have previously untreated locally advanced non-metastatic (M0) TNBC and hormone receptor-low/HER2-negative 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, N0-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. Must have a negative pregnancy test obtained within 3 days before starting therapy. Patients must not be breastfeeding.
10. 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.
11. 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 (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs, with exception of hydroxychloroquine (Plaquenil®)) in subjects planning for pembrolizumab use.
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.

Primary outcomes:
measure: Pathological complete response rate
timeFrame: During surgery
Secondary outcomes:
measure: Event free survival
timeFrame: 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
measure: Quality of life from patient-report outcome
timeFrame: At Screening phase, at Treatment 1 cycle 4 day 1 ( each cycle is 14 days or 21 days) , at Treatment 2 cycle 4 day 1 (each cycle is 14 days or 21 days), through study completion, an average of 5 years
measure: Estradiol
timeFrame: 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
measure: Follicle stimulating hormone
timeFrame: 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
measure: Luteinizing hormone
timeFrame: 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
measure: Tumor microenvironment changes after neoadjuvant chemotherapy with/without ovarian suppression
timeFrame: 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 14 days or 21 days), through study completion, an average of 5 years
measure: Pathological complete response by tumor infiltrating lymphocyte
timeFrame: During surgery
measure: Residual cancer burden
timeFrame: During surgery
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
timeFrame: up to 32 weeks
measure: Breast cancer quality of life from patient-report outcome
timeFrame: At Screening phase, at Treatment 1 cycle 4 day 1 ( each cycle is 14 days or 21 days) , at Treatment 2 cycle 4 day 1 ( each cycle is 14 days or 21 days), through study completion, an average of 5 years
measure: Event free survival by tumor infiltrating lymphocyte
timeFrame: 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.
Other outcomes:
Locations:
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
Study officials:
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