Trilaciclib in Patients With Early-Stage HR-negative Breast Cancer Receiving Adjuvant Chemotherapy

Study Overview
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Brief Summary
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The goal of this multicenter, two-cohort, exploratory clinical trial is to evaluate patients with early stage hormone receptor-negative breast cancer receiving standard adjuvant chemotherapy after surgery. The main question it aims to answer is: • The efficacy and safety of trilaciclib administered before standard adjuvant chemotherapy regimen using the incidence of grade 3/4 neutropenia as the primary efficacy endpoint. Participants will divide into two treatment cohorts according to molecular typing type: Cohort A will be planned to include post-operative triple-negative breast cancer(TNBC) patients with lymph node positive or tumor > 2 cm treated with trilaciclib combined with epirubicin and cyclophosphamide followed by weekly paclitaxel; Cohort B will be planned to include HER2-positive/HR-negative breast cancer patients with axillary node positive or tumor > 2 cm treated with trilaciclib combined with docetaxel, carboplatin and trastuzumab with or without pertuzumab.

Official Title
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A Prospective, Multi-cohort, Exploratory Phase II Study of Trilaciclib Combined With Standard Chemotherapy in The Adjuvant Treatment of Hormone Receptor (HR) Negative Breast Cancer

Conditions
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Breast Neoplasms

Intervention / Treatment
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* Drug: Trilaciclib
* Drug: Epirubicin
* Drug: Cyclophosphamide
* Drug: Paclitaxel
* Drug: Docetaxel
* Drug: Carboplatin
* Drug: Trastuzumab
* Drug: Pertuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age ≥ 18 years; breast cancer meets the following criteria: Histologically or cytologically confirmed and adequately resected non-metastatic primary invasive breast cancer; Cohort A only: ER, PR negative (< 1% nuclear staining as assessed by immunohistochemistry [IHC]), HER2 negative (HER2/CEP17 ratio < 2.0 or mean HER2 gene copy number < 4 signals/nucleus detected by IHC 0 or 1 + or in situ hybridization [ISH]); patients with concurrent bilateral invasive disease met the inclusion criteria if both lesions were HR negative/HER2 negative. Cohort B only: ER, PR negative (< 1% nuclear staining as assessed by immunohistochemistry [IHC]); HER2 positive: HER2/CEP17 ratio ≥ 2.0 or HER2 gene copy number ≥ 4 signals/nucleus detected by IHC 3 + and ISH; HER2 gene copy number ≥ 6 signals/nucleus detected by IHC 3 + or 2 + and ISH); patients with concurrent bilateral invasive disease met the inclusion criteria if both lesions were HR negative/HER2 positive. Subjects must have positive lymph nodes or tumors > 2 cm; The interval between radical surgery and the first dose ≤ 60 days; Eastern Cooperative Oncology Group (ECOG) performance score 0-1; have appropriate organ function, meet the following criteria: (1) have appropriate bone marrow function: Hb ≥ 100 g/L (no ESA and blood transfusion within 14 days before the first dose); absolute neutrophil count (ANC) ≥ 2 × 10^9/L (no G-CSF within 14 days before the first dose); platelet count ≥ 100 × 10^9/L (no rhTPO/rhIL-11 and platelet transfusion within 14 days before the first dose); (2) appropriate liver and kidney function: alanine aminotransferase (ALT) ≤ 2.5 × upper limit of normal (ULN), aspartate aminotransferase (AST) ≤ 2.5 × ULN, total bilirubin (TBIL) ≤ 1.5 × ULN, serum creatinine ≤ 1.5 × ULN, endogenous creatinine clearance > 50 ml/min (Cockcroft-Gault formula); (3) appropriate cardiac function: left ventricular ejection fraction (LVEF) ≥ 55%; Non-hematologic toxicities from prior surgical procedures recovered to ≤ Grade 1 or baseline (except alopecia); Females of childbearing potential agree to practice reliable contraception during the clinical trial and have a negative serum or urine pregnancy test within 7 days prior to dosing; Voluntarily join this study and sign informed consent, have good compliance and are willing to cooperate with follow-up. Exclusion Criteria: Prior neoadjuvant therapy (including chemotherapy, targeted therapy, immunotherapy, or radiotherapy); History of other malignancy within 5 years prior to first dose, except basal cell carcinoma and cervical carcinoma in situ; Any T4 or N2 or known N3 or M1 breast cancer; Subjects who cannot receive or tolerate postoperative chemotherapy for various reasons; Heart disease ineligible for epirubicin, docetaxel, trastuzumab/pertuzumab: Any documented history of myocardial infarction, congestive heart failure Angina pectoris requiring antianginal medication Grade 3 or 4 cardiac arrhythmia (NCI CTCAEv5.0) Clinically significant valvular heart disease; Poorly controlled hypertension (systolic blood pressure > 180 mmHg and/or diastolic blood pressure > 100 mmHg) Known history of hypersensitivity to the drug components of this protocol; Any other condition that, in the opinion of the investigator, would make the patient inappropriate for participation in this study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A: Triple-negative Breast Cancer<br>Cohort A Administered Trilaciclib in Combination with Chemotherapy(EC-wP) | Drug: Trilaciclib<br>* 240 mg/m2, intravenous drip over 30 min within 4 hours before chemotherapy administration on the same day<br>* Other names: G1T28;Drug: Epirubicin<br>* 90 mg/m2, intravenous drip, d1, Q3W, 4 cycles.<br>Drug: Cyclophosphamide<br>* 600 mg/m2, intravenous drip, d1, Q3W, 4 cycles.<br>Drug: Paclitaxel<br>* 80 mg/m2, intravenous drip, d1,8,15, Q3W, 4 cycles.<br>|
| Experimental: Cohort B: ER-negative PR-negative Her2-positive Breast Cancer<br>Cohort B Administered Trilaciclib in Combination with Chemotherapy(TCbH±P) | Drug: Trilaciclib<br>* 240 mg/m2, intravenous drip over 30 min within 4 hours before chemotherapy administration on the same day<br>* Other names: G1T28;Drug: Docetaxel<br>* 75 mg/m2, intravenous drip, d1, Q3W, 6 cycles.<br>Drug: Carboplatin<br>* area under curve(AUC) = 6, intravenous drip, d1, Q3W, 6 cycles.<br>Drug: Trastuzumab<br>* 8 mg/kg in Cycle 1, 6 mg/kg in subsequent cycles, intravenous drip, d1, Q3W, for 1 year.<br>Drug: Pertuzumab<br>* 840mg in Cycle 1, 420mg in subsequent cycles, intravenous drip, d1, Q3W, for 1 year.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of Grade 3/4 neutropenia | Proportion of subjects with at least one absolute neutrophil count (ANC) < 1.0 × 10^9/L enrolled and treated with at least one dose of trilaciclib | Up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neutrophil-related myeloprotective effects | Occurrence of febrile neutropenia adverse events(AEs) , and occurrence of Granulocyte colony-stimulating factor(G-CSF) administration | Up to 24 weeks | 
| Red blood cell(RBC) -related myeloprotective effects | Occurrence of Grade 3/4 decrease of hemoglobin, occurrence and number of RBC transfusions on/after Week 5, and occurrence of erythropoiesis-stimulating agent(ESA) administration | Up to 24 weeks | 
| Platelet-related myeloprotective effects | Occurrence of Grade 3/4 decrease of platelets, occurrence and number of platelet transfusions, and occurrence of rhTPO/Recombinant human interleukin-11(rhIL-11) administration | Up to 24 weeks | 
| Myeloprotective Effects | Hospitalization due to chemotherapy-induced myelosuppression, dose reductions and delays, relative dose intensity(RDI) of chemotherapeutic agents | Up to 24 months | 
| Safety and tolerability | Incidence of Treatment-Emergent Adverse Events as per CTCAE version 5.0 | Up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Trilaciclib; HR-Negative Breast Cancer; Adjuvant Therapy