The Trial Comparing Dose-dense AC-T With TP as Adjuvant Therapy for TNBC With Homologous Recombination Repair Deficiency

Sponsor

Chinese Academy of Medical Sciences (Other)

Overall Status

Recruiting

CT.gov ID

NCT03876886

Collaborator

(none)

200

Enrollment

Location

Arms

69.3

Anticipated Duration (Months)

2.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this trial is to compare the 3-year disease-free survival of dose-dense epirubicin and cyclophosphamide followed by paclitaxel with paclitaxel plus carboplatin as adjuvant therapy for triple-negative breast cancer with homologous recombination repair deficiency.

The other purpose of this trial is to observe the patient's tolerance.

Condition or Disease	Intervention/Treatment	Phase
Triple Negative Breast Cancer	Drug: Epirubicin Drug: Cyclophosphamide Drug: Paclitaxel Drug: Carboplatin Drug: Paclitaxel	Phase 3

Detailed Description

Triple-negative breast cancer (TNBC) lack the expression of oestrogen receptor (ER), progesterone receptor(PR) and human epidermal growth factor receptor 2 (HER2) , and characterizes an aggressive behavior with higher risk of recurrence and death compared to other breast cancer subtypes. Little therapeutic progress has been made in adjuvant therapy in TNBC during the past decades and the standard of care is still missing.

Pre-clinical and clinical data suggest that platinum-based regimens represent an emerging therapeutic option for selected patients with homologous recombination repair deficiency (HRD). The HR system is critical in regulating and maintaining genome stability, and is one of the most commonly altered systems in TNBCs, up to 15-20% TNBC patients carry germline BRCA1/2 mutations. Other HR genes included PALB2, RAD51 etc. Tumors that harbor HRD possess an increased burden of genomic aberrations and lesions, and have been shown to have increased sensitivity to DNA crosslinking agents such as platinum salts. Platinum-based regimens have been encouraging in TNBC patients with HRD, given increases in both pathologic complete response (pCR) rates in neoadjuvant trials and objective response rates(ORR) in metastatic diseases. Further information are needed on how platinum-containing therapies affect long-term outcomes in the adjuvant setting.

In this trial, the investigators intend to compare the 3-year disease-free survival (DFS) of dose-dense epirubicin and cyclophosphamide followed by paclitaxel with paclitaxel plus carboplatin as adjuvant therapy in high-risk node-negative or node-positive TNBC patients with HRD. The other purpose of this trial is to observe the participants' tolerance.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

200 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Randomized Phase Ⅲ Trial Comparing Dose-dense Epirubicin and Cyclophosphamide Followed by Paclitaxel With Paclitaxel Plus Carboplatin as Adjuvant Therapy for Triple-negative Breast Cancer With Homologous Recombination Repair Deficiency

Actual Study Start Date :

Feb 22, 2019

Anticipated Primary Completion Date :

Feb 1, 2024

Anticipated Study Completion Date :

Dec 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: AC-T(dose-dense) A: epirubicin, pharmorubicin (EPI) C: cyclophosphamide (CTX） T: paclitaxel (PTX）	Drug: Epirubicin Epirubicin 90mg/m2 iv d1 or divide into two days Drug: Cyclophosphamide cyclophosphamide600mg/m2 iv d1,q14d4cycles;with G-CSF support: 3ug/kg ih Drug: Paclitaxel* paclitaxel 175mg/m2 iv d1, q14d*4cycles
Experimental: TP(dose-dense) T: paclitaxel (PTX） P: carboplatin (CBP)	Drug: Carboplatin carboplatin AUC=3 iv d2, q14d8cycles;with G-CSF support: 3ug/kg ih Drug: Paclitaxel* paclitaxel 175mg/m2 iv d1, q14d*8cycles

Arm

Intervention/Treatment

Active Comparator: AC-T(dose-dense)

A: epirubicin, pharmorubicin (EPI) C: cyclophosphamide (CTX） T: paclitaxel (PTX）

Drug: Epirubicin

Epirubicin 90mg/m2 iv d1 or divide into two days

Drug: Cyclophosphamide

cyclophosphamide600mg/m2 iv d1,q14d*4cycles;with G-CSF support: 3ug/kg ih

Drug: Paclitaxel

paclitaxel 175mg/m2 iv d1, q14d*4cycles

Experimental: TP(dose-dense)

T: paclitaxel (PTX） P: carboplatin (CBP)

Drug: Carboplatin

carboplatin AUC=3 iv d2, q14d*8cycles;with G-CSF support: 3ug/kg ih

Drug: Paclitaxel

paclitaxel 175mg/m2 iv d1, q14d*8cycles

Outcome Measures

Primary Outcome Measures

3-year disease-free survival [Three years]
The participants will be followed by the telephone for the duration, an expected average of 3 years.

Secondary Outcome Measures

Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [Three years]
Incidence of neutropenic fever; Incidence of grade 3-4 side effects; Toxicity assessed by NCI CTCAE v5.0

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 60 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

18-60 years
Histologically confirmed adenocarcinoma of the breast, complete tumor removal by either modified radical mastectomy or local excision plus axillary lymph node dissection (i.e., breast conservation therapy) or sentinel node biopsy. (Tumor-free margins at least 1 mm for both invasive and noninvasive carcinoma except for lobular carcinoma in situ (less than 1 mm allowed);
Histologically confirmed ER(-) PR(-) and HER-2(IHC(immunohistochemistry) 0-1+ or FISH (fluorescence in situ hybridization) negative)
Next-generation sequencing confirmed homologous recombination repair deficiency
Meet one of the following criteria:

(1) Positive axillary lymph nodes; (2) Negative axillary lymph nodes with at least one of the following risk factors: age<= 35 years; grade III; infiltrative tumor size > 2cm; intravascular tumor embolus; Ki-67>=50%.

Eastern Cooperative Oncology Group (ECOG) Performance Score 0-1 7. Adequate bone marrow reserve with ANC > 1500, HGB > 9g/dL and platelets > 100,000.
Adequate renal function with serum creatinine < 2.0. 9. Adequate hepatic reserve with serum bilirubin < 2.0, AST/ALT < 2X the upper limit of normal, and alkaline phosphatase < 5X the upper limit of normal. Serum bilirubin > 2.0 is acceptable in the setting of known Gilbert's syndrome.
Not pregnant, and on appropriate birth control if of child-bearing potential.
Written informed consent according to the local ethics committee requirements.

Exclusion Criteria:

Prior systemic treatment of breast cancer, including chemotherapy;
Metastatic breast cancer;
Patients with medical conditions that indicate intolerant to adjuvant therapy and related treatment, including uncontrolled pulmonary disease, diabetes mellitus, severe infection, active peptic ulcer, coagulation disorder, connective tissue disease or myelo-suppressive disease;
Has active hepatitis B or hepatitis C with abnormal liver function tests (LFTs) or is known to be HIV positive;
Contraindication for using dexamethasone;
History of congestive heart failure, uncontrolled or symptomatic angina pectoris, arrhythmia or myocardial infarction; poorly controlled hypertension (systolic BP>180 mmHg or diastolic BP>100 mmHg);
Pregnant or breast feeding.
Hepatic, renal, or bone marrow dysfunction as detailed above.
Known severe hypersensitivity to any drugs in this study;
Treatment with any investigational drugs within 30 days before the beginning of study treatment.