Clinical trial NCT03876886: The Trial Comparing Dose-dense AC-T With TP as Adjuvant Therapy for TNBC With Homologous Recombination Repair Deficiency
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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Triple Negative Breast Cancer
Keywords: homologous recombination deficiency;adjuvant chemotherapy;anthracycline;taxanes;platinum
Lead sponsor: ChineseAMS
Sponsor class: UNKNOWN
First posted: 2019-03-15
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: Inclusion Criteria:

1. 18-60 years
2. 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);
3. Histologically confirmed ER(-) PR(-) and HER-2(IHC(immunohistochemistry) 0-1+ or FISH (fluorescence in situ hybridization) negative)
4. Next-generation sequencing confirmed homologous recombination repair deficiency
5. 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%.

6. Eastern Cooperative Oncology Group (ECOG) Performance Score 0-1 7. Adequate bone marrow reserve with ANC \> 1500, HGB \> 9g/dL and platelets \> 100,000.

8. 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.

10. Not pregnant, and on appropriate birth control if of child-bearing potential.

11. Written informed consent according to the local ethics committee requirements.

Exclusion Criteria:

1. Prior systemic treatment of breast cancer, including chemotherapy;
2. Metastatic breast cancer;
3. 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;
4. Has active hepatitis B or hepatitis C with abnormal liver function tests (LFTs) or is known to be HIV positive;
5. Contraindication for using dexamethasone;
6. 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);
7. Pregnant or breast feeding.
8. Hepatic, renal, or bone marrow dysfunction as detailed above.
9. Known severe hypersensitivity to any drugs in this study;
10. Treatment with any investigational drugs within 30 days before the beginning of study treatment.

Primary outcomes:
measure: 3-year disease-free survival
timeFrame: Three years
Secondary outcomes:
measure: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
timeFrame: Three years
Other outcomes:
Locations:
city: Beijing
country: China
facility: National Cancer Center, Cancer Hospital/Chinese Academy of Medical Sciences and Peking Union Medical College
state: Beijing
Study officials:
References: