The Efficacy and Safety of Eutideron, Etoposide, and Bevacizumab in Patients With Brain Metastases From Breast Cancer.

A Single-arm, Open-label， Phase Ⅱ Clinical Trial of Eutideron, Etoposide Combined With Bevacizumab for Breast Cancer Patients With Brain Metastases

This study was a single-arm, open-label, phase II study of breast cancer patients with brain metastases. Eligible patients received a regimen of eutidrone(30mg/m2/d,iv,d1-5,21d/cycle), etoposide(30mg/m2/d,iv,d1-3,21d/cycle), and bevacizumab (10mg/kg,d1,21d/cycle).At least 4 to 6 cycles were administered, and if patients had a response or stable disease, bevacizumab was used as maintenance therapy until disease progression or intolerable toxicity.

Study Overview

• Status: Recruiting
• Conditions: Mammary Neoplasms, Human
• Intervention / Treatment: Drug: eutidrone etoposide bevacizumab

Detailed Description

The natural survival time of breast cancer patients with brain metastases is short and the prognosis is poor. Although the treatment is progressing, but it is still limited. The current domestic guidelines still recommend local therapy as a priority treatment strategy. At the same time, about 80% of patients with brain metastasis will progress to extracranial metastasis, so superior systemic treatment is particularly important, but very lacking.Therefore, new systematic therapeutic drugs are urgently needed .Eutiderone is a new generation of epirubicin anti-tumor drug with good efficacy and safety. In pre-clinical studies, it has been shown that the drug concentration in most tissues is higher than that in plasma, and the concentration of eutiderone in brain tissue is higher, indicating that the drug is easy to cross the blood-brain barrier.

• Study Type: Interventional
• Enrollment (Anticipated): 43
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Yehui Shi, MD,Phd; Phone Number: 18622221183; Email: shiyehui@tjmuch.com

Study Locations

• China
  • Tianjin
    • Tianjin, Tianjin, China, 300060
      • Recruiting
      • Yehui Shi
      • Contact: Yehui Shi; Phone Number: 18622221183; Email: shiyehui@tjmuch.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Signed informed consent form.
• Female,>18.
• Histologically or cytologically confirmed recurrent metastatic breast cancer.
• ECOG:0-2.
• There was at least one measurable lesion in the central nervous system.
• Based on screening brain magnetic resonance imaging (MRI), patients with CNS must meet one of the following conditions：
• Untreated brain metastases from breast cancer do not require immediate local treatment.
• Previously treated breast cancer brain metastases that have progressed after previous central nervous system local treatment as assessed by the investigator and that do not have clinical features requiring immediate local treatment.
• Previous anti-HER2 therapy and TKI therapy were required for HER2+ patients.
• Patients who had not received chemotherapy, radiotherapy, surgery, targeted therapy or immunotherapy within 4 weeks before enrollment.
• All toxicity in patients associated with previous antitumor therapy must be restored to ≤ grade 1 (CTCAE v5.0). However, patients with any grade of alopecia were allowed.
• Routine blood tests were normal within 1 week before enrollment (according to the normal range at the participating laboratory):White blood cell count (WBC) ≥ 3.0 × 109/L; Neutrophil count (ANC) ≥ 1.5 × 109/L; Platelet count (PLT) ≥ 100 × 109/L; Hemoglobin ≥ 9.0 g/dL; patients could receive blood transfusions or erythropoietin to meet this criterion.
• Liver and kidney function were basically normal within 1 week before enrollment (based on the normal values of the participating laboratory):Total bilirubin (TBIL) ≤ 2.5× upper limit of normal value (ULN); Alanine aminotransferase (SGPT/ALT) ≤2.5×ULN (≤5×ULN in patients with liver metastases); Aspartate aminotransferase (SGOT/AST) ≤2.5×ULN (≤5×ULN in patients with liver metastases); Creatinine clearance (Ccr) ≥60 ml/min
• Male or female patients of childbearing potential had to consent to use an effective method of contraception, such as dual barrier methods, condoms, oral or injectable contraceptives, intrauterine devices, etc., during the study period and up to 90 days after the last study medication was taken. Female patients of reproductive age had to have a negative blood or urine pregnancy test before enrollment.
• Life expectancy ≥ 12 weeks.

Exclusion Criteria:

• Other malignant tumors (including primary brain or leptomeningeal related tumors) within the past 5 years, except cured basal cell carcinoma of the skin and carcinoma in situ of the cervix;
• Previous anti-tumor therapy, including chemotherapy, radical radiotherapy, hormone therapy, biological therapy, immunotherapy or anti-tumor traditional Chinese medicine therapy within 4 weeks before initiation of study treatment.
• Patients had previously used eutidrone injection, etoposide, or bevacizumab.
• Patients had undergone major organ surgery (excluding needle biopsies) or major trauma within 4 weeks before the first dose of the study drug, or required elective surgery during the trial.
• Patients with ≥grade 3 neurosystem-related severe adverse reactions after previous use of anti-microtubules.
• Patients with any untreated > 2.0cm brain injury, unless discussed with the investigator and approved for registration.
• Systemic corticosteroids were continued to control symptoms of brain metastases at a total daily dose of >2mg dexamethasone (or equivalent). However, patients with chronic stable doses ≤2mg daily of dexamethasone (or equivalent) may be discussed and approved by the investigator.
• Any brain lesion deemed to require immediate local treatment, including (but not limited ) increased lesion size at anatomical sites or possible treatment-related edema, may pose a risk to the patient (e.g.brain stem lesions). Patients received local treatment were still eligible for study based on lesions identified by screening contrast brain MRI according to the criteria described in the CNS inclusion criteria.
• More than 2 seizures within 4 weeks before enrollment.
• Poor control of hypertension; Or a previous history of hypertensive crisis or hypertensive encephalopathy.
• Patients had a history of hemoptysis within 6 months before enrollment. Or evidence of bleeding tendency or significant coagulopathy within the past 1 month.
• Currently receiving full-dose warfarin or equivalent, or aspirin (325mg/ day) within 10 days
• The need for major surgery, open biopsy, or major trauma was anticipated within 28 days or during the course of the study.
• Patients with a history of abdominal fistula or gastrointestinal perforation within the previous 6 months; The presence of an unhealed wound, active ulcer, or untreated fracture; Pregnant or lactating women.
• Patients with a history of psychotropic drug abuse and inability to abstain or with mental disorders.
• Other nonmalignant systemic diseases (cardiovascular, renal, liver, etc.) that were treated by any treatment regimen or prevented follow-up were excluded.
• Known or suspected allergies to any of the study drugs or excipients.
• No brain MRI for any reason.
• Any other condition considered by the investigator to be unsuitable for participation in the trial.
• Other situations in which corticosteroid use is prohibited.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: eutidrone+ etoposide+ bevacizumab; Eligible patients received a regimen of eutidrone(30mg/m2/d,iv,d1-5,21d/cycle), etoposide(30mg/m2/d,iv,d1-3,21d/cycle), and bevacizumab (10mg/kg,d1,21d/cycle).At least 4 to 6 cycles were administered, and if patients had a response or stable disease, bevacizumab was used as maintenance therapy until disease progression or intolerable toxicity.

Drug: eutidrone etoposide bevacizumab; Eligible patients received a regimen of eutidrone(30mg/m2/d,iv,d1-5,21d/cycle), etoposide(30mg/m2/d,iv,d1-3,21d/cycle), and bevacizumab (10mg/kg,d1,21d/cycle).At least 4 to 6 cycles were administered, and if patients had a response or stable disease, bevacizumab was used as maintenance therapy until disease progression or intolerable toxicity.MRI of the brain with contrast enhancement was performed at baseline and every 6 weeks after enrollment; thereafter, patients with stable disease or a response could be assessed at a reduced frequency to every 9 weeks; central nervous system and noncentral nervous system lesions were assessed according to RANO-BM criteria and RECIST v1.1 criteria until disease progression, respectively.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CNS Objective response rate (CNS-ORR)	The proportion of patients with complete response (CR) and partial response (PR) evaluated as the best response observed from enrollment to progression of all CNS target lesions assessed according to RANO-BM criteria among the total number of patients who could be evaluated.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CNS Clinical benefit rate(CNS-CBR)	Percentage of patients who achieved complete response (CR), partial response (PR), or stable disease (SD) in all CNS target lesions assessed by RANO-BM criteria within 12 weeks.	3 months
CNS Progression-free survival (CNS-PFS)	Time from enrollment to the first radiographic documented disease progression (PD) of all CNS target lesions (RANO-BM criteria) or death from any cause without progression was recorded.	36 months
Objective response rate (ORR)	Partial response is defined as a decrease by 30% or more in sums of longest diameter of measurable target lesions	12 months
Progression-free survival（PFS）	Time from enrollment to the first radiographically confirmed disease progression (PD) (RECIST 1.1 criteria) or death from any cause without documented progression	36 months
Overall survival (OS)	Time from the enrollment to death of any cause	36 months

Collaborators and Investigators

• Sponsor: Tianjin Medical University Cancer Institute and Hospital
• Investigators: Principal Investigator: Yehui Shi, MD,Phd, Tianjin Medical University Cancer Institute and Hospital

Study record dates

Study Major Dates

• Study Start (Actual): July 20, 2022
• Primary Completion (Anticipated): July 20, 2023
• Study Completion (Anticipated): July 20, 2025

Study Registration Dates

• First Submitted: February 19, 2023
• First Submitted That Met QC Criteria: March 10, 2023
• First Posted (Actual): March 23, 2023

Study Record Updates

• Last Update Posted (Actual): March 23, 2023
• Last Update Submitted That Met QC Criteria: March 10, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Central Nervous System Neoplasms; Nervous System Neoplasms; Breast Neoplasms; Brain Neoplasms; Mammary Neoplasms, Animal; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Etoposide; Bevacizumab
• Other Study ID Numbers: UTD-1-BM-II

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
• product manufactured in and exported from the U.S.: No