Bevacizumab, Etoposide and Cisplatin Followed by Whole Brain Radiotherapy in Breast Cancer With Brain Metastases (A-Plus)

Randomized Phase II Study of Induction Bevacizumab, Etoposide and Cisplatin Followed by Whole Brain Radiotherapy (WBRT) Versus WBRT Alone in Breast Cancer With Untreated Brain Metastases

The primary objective of A-PLUS trial is to evaluate and compare the efficacy of induction BEEP (bevacizumab preconditioning followed by etoposide and cisplatin) followed by whole bran radiotherapy (WBRT) with WBRT alone in the controlling of brain metastases (BM) in metastatic breast cancer (MBC) patients who have not previously received WBRT.

In past 2 years, the research team has demonstrated that BEEP regimen is a highly effective treatment for brain metastases of breast cancer progressing from WBRT by a multi-center phase II study (ClinicalTrials.gov Identifier: NCT01281696). The basic concept of preconditioning, as referred to starting bevacizumab 1 day before chemotherapy, is that the effect of bevacizumab induced tumor vascular normalization takes time to mature.

The investigators hypothesized that as induction BEEP decreased the size of brain tumors, the effectiveness of WBRT would be maximized. The investigators expect this integrated approach will do greater benefit to MBC patients with BM, irrespective of subtype.

Study Overview

• Status: Active, not recruiting
• Conditions: Breast Cancer; Brain Metastases
• Intervention / Treatment: Drug: BEEP regimen

Detailed Description

Brain metastasis (BM) occurs in about 20% to 35% of metastatic breast cancer (MBC) patients. In contrast to recent advances in systemic treatment of MBC, there is much room for improvement in treatment of BM. At present, the standard treatment for inoperable/not suitable for radiosurgery BM is whole-brain radiotherapy (WBRT), but with only a median overall survival (OS) of 6 to 12 months and a high brain relapse rate ranging from 30% to 100%.

In MBC, 70% to 80% of patients with BM are presented with more than two brain metastatic tumors and are not candidate for both surgical treatment and stereotactic radiosurgery (SRS). Unlike patients with solitary or oligo-brain metastatic tumors, for whom the addition of local treatments such as surgery or SRS has been shown to improve OS and relapse rate; for patients with multiple brain metastases, WBRT remained the only standard treatment and improvements are desperately awaited.

Brain was once considered as a "sanctuary" area for systemic drugs due to the protection of blood-brain-barrier (BBB). Although some preclinical studies suggest that the BBB could be disrupted during the growth of brain metastatic tumor, the amount of chemotherapy drugs be delivered to brain tissue was still far lower than that could be achieved in serum. Bevacizumab, a vascular endothelial growth factor antibody, has shown the ability to "normalize" the peri-tumoral vessels in preclinical models. The investigators hypothesized that with the addition of bevacizumab, the chemotherapy drugs-etoposide and cisplatin, which were shown also to have some activity for BM-will be delivered more efficiently into the once "sanctuary" brain parenchyma, thus increasing the efficacy of BM treatment.

Recently, the research team have demonstrated that bevacizumab preconditioning followed by etoposide and cisplatin (BEEP) is a highly effective treatment for brain metastases of breast cancer progressing from radiotherapy by a multi-center phase II study. The basic concept of preconditioning, as referred to starting bevacizumab 1 day before chemotherapy, is that normalization effect takes time to mature. In that study, 35 patients were enrolled. Twenty seven patients (77.2%; 95%CI 59.9-89.6) achieved brain tumor volumetric response, defined as a ≥50% reduction in the volumetric sum of all measurable brain lesions in the absence of increasing steroid use, development of new brain lesion, or progressive neurologic symptoms. With a median follow-up of 11.0 months, the median CNS progression free survival (PFS) was 6.7 months (95% CI 5.1 to 8.3 months), and OS was 9.4 months (95% CI 7.3 to 11.5 months).

At present, lapatinib is the only molecular targeted agent proven effective for MBC patients with BM. The CNS response rate of first-line lapatinib plus capecitabine was 65% in WBRT-naïve, HER2-positive MBC patients with BM. However, the median CNS PFS is still disappointingly short at 5.5 months and the result is limited to MBC patients who are HER2-positive.

It has been demonstrated that brain tumor size is a predictor of WBRT failure. Given the high response rate of BEEP for BM in our phase II trial, the investigators hypothesized that as induction BEEP decreased the size of BM, the effectiveness of WBRT would also be enhanced. This integrated approach will do greater benefit to MBC patients with BM, irrespective of subtype. Hence, the investigators plan to conduct this randomized phase II trial to evaluate the efficacy of induction BEEP followed by WBRT.

Sub study of A-PLUS: A Integrated Study of MRI and PET of The Brain in Evaluation of Neurocognitive Outcomes of Patients with Brain Metastasis Treated by Radiotherapy and Chemotherapy.

The participants of A-PLUS trial may be enrolled in an additional study of this trial. This additional prospective study aims to investigate the neurocognitive outcomes of patients with brain metastases treated by radiotherapy and chemotherapy. The evaluations include neurocognitive assessments, serial MRI and FDG PET-CT (Integrated MR-PET) at before and after the study treatment. A total of 80 participants will be enrolled. The study protocol was approved by the NTUH REC, No. 201412046MINA.

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Phase 2

Contacts and Locations

Study Locations

• Taiwan
  • Kaohsiung, Taiwan
    • Kaohsiung Chang Gung Memorial Hospital
  • New Taipei City, Taiwan
    • Shuang Ho Hospital
  • Taichung, Taiwan
    • China Medical University Hospital
  • Taipei, Taiwan, 100
    • National Taiwan University Hospital
  • Taipei, Taiwan
    • Mackay Memorial Hospital
  • Taipei, Taiwan
    • Taipei Veterans General Hospital
  • Taipei, Taiwan, 114
    • Tri-Service General Hospital
  • Taoyuan, Taiwan
    • Chang Gung Memorial Hospital-Linkou

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion criteria:

• A histological confirmed invasive breast cancer.
• At least one measurable brain metastatic tumor. If the measurable brain lesion has previously received stereotactic radiosurgery, the tumor must be a progressive lesion after radiosurgery.
• Patients who had not received WBRT.
• Patients with HER2/neu overexpression or amplification and had received trastuzumab before the diagnosis of BM will be allowed but will be informed about other available treatment options such as lapatinib plus capecitabine.
• Karnofsky performance score (KPS) higher or equal to 30%.
• Patients must have adequate organ function and marrow reserve measured within 14 days prior to randomization
• Age 20 to 75 years.
• Patient's life expectancy is more than 3 months.
• All women of childbearing potential must have a negative pregnancy test obtained within 72 hours before starting therapy.
• Patients with reproductive potential must use effective contraception (hormone or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 6 months after the completion of therapy.
• Patients (or a surrogate) must be able to comply with study procedures and sign informed consent.

Exclusion criteria:

• Prior therapy with bevacizumab, sorafenib, sunitinib, or other VEGF pathway-targeted therapy.
• Patients who have history of disease progression or disease developed during prior cisplatin treatment.
• Patients who had leptomeningeal metastasis, either diagnosed by brain imaging study or confirmed by cerebrospinal fluid cytology examination.
• Patients who are eligible for and willing to receive brain surgery or stereotactic radiosurgery (SRS) as the initial treatment of BM.
• History or evidence of inherited bleeding diathesis or coagulopathy with the risk of bleeding.
• History of thrombotic disorders.
• Active gastrointestinal bleeding.
• Patients with a history of self-reported intra-cranial hemorrhage or evidence of bleeding in previous cranial imaging.
• Patients with clinical signs or symptoms of gastrointestinal obstruction and who require parenteral hydration and/or nutrition because of obstruction.
• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months of first dose of bevacizumab.
• Clinically significant peripheral artery occlusive disease.
• Arterial thromboembolic event within the past 6 months, including transient ischemic attack, cerebrovascular accident, unstable angina, or myocardial infarction.
• History of gross hemoptysis (e.g., ≥ 1 teaspoon of bright red blood).
• Other malignancy within 5 years except cured basal cell or squamous cell skin cancer or carcinoma in situ of the cervix.
• Psychiatric illness or social situation that would preclude study compliance.
• Serious non-healing wound, ulcer, or bone fracture.
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to enrollment.
• Prior minor surgery within 7 days.
• Concurrent chronic daily aspirin (> 325 mg/day), dipyridamole, ticlopidine, clopidogrel, cilostazol, non-steroidal anti-inflammatory agents known to inhibit platelet function.
• Concurrent therapeutic anticoagulation, but prophylactic anti-coagulation of venous access devices is allowed.
• History of allergic reaction to compounds of similar chemical composition to the study drugs.
• Pregnancy or lactation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Inductional BEEP regimen; Induction BEEP regimen: Every 3 weeks a cycle for a total of 3 cycles (around 2 months); Bevacizumab 15mg/kg IVF on D1; Etoposide 70 mg/m2 IVF QD, D2-4; Cisplatin 70 mg/m2 IVF on D2 WBRT: 3000cGy in 10 fractions	Drug: BEEP regimen; Bevacizumab 15mg/kg IVF on D1, Etoposide 70 mg/m2 IVF QD, D2-4, Cisplatin 70 mg/m2 IVF on D2, repeat every 3 weeks, for 3 cycles; Other Names: Cisplatin; Bevacizumab; Etoposide
No Intervention: WBRT alone; standard WBRT: 3000cGy in 10 fractions

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Brain-specific progression free survival (BS-PFS)	To evaluate and compare the brain-specific progression free survival (BS-PFS) of the two treatment arms based on RECIST 1.1.	2.5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The 2-month brain-specific objective response rate (BS-ORR)	To compare the 2-month brain-specific objective response rate (BS-ORR) of the two treatment arms based on volumetric analysis (CNS composite response criteria).	2 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
The BS-PFS based on volumetric analysis (CNS composite response criteria)	To compare the BS-PFS of the two treatment arms based on volumetric analysis (CNS composite response criteria).	2.5 years
The 8-month BS-PFSR based on volumetric analysis (CNS composite response criteria)	To compare the 8-month BS-PFSR of the two treatment arms based on volumetric analysis (CNS composite response criteria).	8 months
The BS-ORR based on volumetric analysis (CNS composite response criteria)	To evaluate and compare the BS-ORR of the two treatment arms based on volumetric analysis (CNS composite response criteria).	5 months
The 8-month BS-PFSR based on RECIST 1.1	To compare the 8-month BS-PFSR of the two treatment arms based on RECIST 1.1.	8 months
The progression free survival (PFS) and overall survival (OS)	To observe the difference of the PFS and OS between the two treatment arms.	2.5 years
The extra-CNS tumor progression free survival (PFS) based on RECIST 1.1	To evaluate and compare extra-CNS tumor progression free survival (PFS) of the two treatment arms (and followed by physician/investigator choice of systemic therapy) based on RECIST 1.1.	2.5 years
The time-to-improvement of neurological function	To evaluate the difference of time-to-improvement of neurological function between the two treatment arms.	3 months
Number of participants with adverse events	To evaluate and compare the safety profile of the two treatment arms according CTCAE 4.0.	3 months

Collaborators and Investigators

• Sponsor: National Taiwan University Hospital
• Investigators: Principal Investigator: Yen-Shen Lu, M.D, Ph.D., National Taiwan Unversity Hospital

Study record dates

Study Major Dates

• Study Start (Actual): April 21, 2014
• Primary Completion (Actual): November 1, 2019
• Study Completion (Anticipated): November 1, 2022

Study Registration Dates

• First Submitted: June 25, 2014
• First Submitted That Met QC Criteria: July 3, 2014
• First Posted (Estimate): July 9, 2014

Study Record Updates

• Last Update Posted (Actual): May 7, 2021
• Last Update Submitted That Met QC Criteria: May 6, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: Breast Cancer; Bevacizumab; Chemotherapy; Brain Metastases; Whole Brain Radiotherapy
• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Neoplastic Processes; Central Nervous System Neoplasms; Nervous System Neoplasms; Breast Neoplasms; Neoplasm Metastasis; Brain Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Etoposide; Cisplatin
• Other Study ID Numbers: 201402059MIPD