Bevacizumab, Etoposide and Cisplatin Followed by Whole Brain Radiotherapy in Breast Cancer With Brain Metastases

Breast Cancer Clinical Trial

— A-Plus  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02185352
• Other study ID #: 201402059MIPD
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: April 21, 2014
• Est. completion date: November 2022

Study information

• Verified date: May 2021
• Source: National Taiwan University Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 120
• Est. completion date: November 2022
• Est. primary completion date: November 1, 2019
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 20 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• Brain Metastases
• Brain Neoplasms
• Breast Cancer
• Breast Neoplasms
• Neoplasm Metastasis
• Neoplasms, Second Primary

Intervention

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

Locations

Country	Name	City	State
Taiwan	Kaohsiung Chang Gung Memorial Hospital	Kaohsiung
Taiwan	Shuang Ho Hospital	New Taipei City
Taiwan	China Medical University Hospital	Taichung
Taiwan	Mackay Memorial Hospital	Taipei
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Taipei Veterans General Hospital	Taipei
Taiwan	Tri-Service General Hospital	Taipei
Taiwan	Chang Gung Memorial Hospital-LinKou	Taoyuan

Sponsors (1)

Lead Sponsor	Collaborator
National Taiwan University Hospital

Country where clinical trial is conducted

Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	Number of participants with adverse events	To evaluate and compare the safety profile of the two treatment arms according CTCAE 4.0.	3 months
Primary	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	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