Carboplatin and Bevacizumab for Progressive Breast Cancer Brain Metastases

Study Description

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Brief Summary:

The purpose of this research study is to determine how well the combination of bevacizumab and carboplatin works in treating breast cancer that has spread to the brain. Bevacizumab is an antibody (a protein that attacks a foreign substance in the body) that is made in the laboratory. Bevacizumab works differently from the way chemotherapy drugs work. Usually chemotherapy drugs attack fast growing cancer cells in the body. Bevacizumab works to slow or stop the growth of cells in cancer tumors by decreasing the blood supply to the tumors. When the blood supply is decreased, the tumors don't get the oxygen and nutrients they need to grow. Carboplatin is in a class of drugs known as platinum-containing compounds and has been approved for use in the treatment of ovarian cancer. Information from other research studies suggests that the combination of bevacizumab with carboplatin may be effective in treating breast cancer.

Condition or disease	Intervention/treatment	Phase
Metastatic Breast Cancer; Breast Cancer; Progressive Breast Cancer	Drug: carboplatin; Drug: bevacizumab; Drug: herceptin	Phase 2

Detailed Description:

Objectives:

Primary

• Objective response rate (CR + PR) in the CNS, by composite criteria, including central volumetric analysis of brain MRI scans

Secondary

• Safety/tolerability
• Progression-free survival
• Clinical benefit (CR, PR, or SD>/=24 weeks)
• Site of first progression (CNS versus non-CNS)
• Overall survival

Exploratory

• Exploratory analysis of the relationship between change in malignancy score, as determined by analysis of modified magnetic resonance angiography (MRA) and PFS
• Exploratory analysis of the relationship between change in malignancy score, as determined by analysis of modified MRA and CNS objective response
• Descriptive analysis of cerebral blood volume/flow, mean transit time, mean vessel diameter, permeability, and diffusion before and after bevacizumab treatment
• Exploratory analysis to examine the association of circulating tumor cell number with overall survival and treatment response
• Exploratory analysis to evaluate CTCs using fluorescence in situ hybridization (FISH) for HER2 gene amplification to examine the relationship between the HER2 status of a patient's primary breast cancer, metastatic lesions, and CTCs
• Exploratory analysis to evaluate HER2-positive CTCs using FISH for EGFR gene amplification to examine the possible mechanisms of resistance driven by EGFR
• Exploratory evaluation of the association of VEGF genotype (derived from candidate single nucleotide polymorphisms) with overall survival, toxicity, and imaging correlatives (i.e. malignancy score)

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	38 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Phase II Trial of Carboplatin and Bevacizumab for Progressive Breast Cancer Brain Metastases
Actual Study Start Date :	November 2009
Actual Primary Completion Date :	January 2014
Actual Study Completion Date :	August 2017

Arms and Interventions

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Arm

Intervention/treatment

Experimental: carboplatin, bevacizumab, trastuzumab (if HER2+); Participants received treatment until disease progression in either CNS or non-CNS site. Cycle duration was 28 days. carboplatin: AUC=5 dose given intravenously on day 8 of cycle one and Day 1 of each subsequent cycle bevacizumab: 15 mg/kg dose given intravenously on day 1 of each cycle trastuzumab*: 6 mg/kg dose given intravenously on day 8 of each cycle for patients with HER2-positive breast cancer only *8mg/kg loading dose in cycle 1 for some participants

Drug: carboplatin; Drug: bevacizumab; Other Name: Avastin; Drug: herceptin; Other Name: trastuzumab

Outcome Measures

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Primary Outcome Measures :

1. Central Nervous System (CNS) Objective Response Rate [ Time Frame: Response was evaluated radiologically at baseline and every 2 cycles on treatment. Treatment duration for this study cohort was a median (range) of 8 cycles (1-20) which approximates months given the 4 week cycle length. ]

   CNS objective response rate is the percentage of participants that achieve CNS complete or partial response as follows:

   CNS complete response (CR) is achieved if all of the following are satisfied:

   • Complete resolution of all measurable (>= 1 cm in longest dimension [LD]) and non-measurable brain metastases
   • No new CNS lesions (defined as any new lesion >= 6 mm in LD)
   • Stable or decreasing steroid dose
   • No new/progressive tumor-related neurologic signs or symptoms
   • No progression of extra-CNS disease as assessed by RECIST

   CNS partial response (PR) is achieved if all of the following are satisfied:

   ->/= 50% reduction in the volumetric sum of all measurable (>/= 1 cm in LD) brain metastases compared to baseline

   • No progression on non-measurable lesions
   • No new CNS lesions (defined as any new lesion >/= 6 mm in LD)
   • Stable or decreasing steroid dose
   • No new/progressive tumor-related neurologic signs or symptoms
   • No progression of extra-CNS disease as assessed by RECIST

Secondary Outcome Measures :

1. Progression-Free Survival [ Time Frame: Disease was evaluated radiologically at baseline and every 2 cycles on treatment. Off treatment, participants were followed every 3 months for progression and overall survival. Duration of follow-up for this study cohort approximated up to 3 years. ]
   Progression-Free Survival (PFS) is defined as the duration of time from start of treatment to time of progression, second cancer, or death, whichever occurs first. PFS is estimated using Kaplan-Meier methods.
2. CNS Best Response [ Time Frame: Response was evaluated radiologically at baseline and every 2 cycles on treatment. Treatment duration for this study cohort was a median (range) of 8 cycles (1-20) which approximates months given the 4 week cycle length. ]

   CNS best response was defined based on standard criteria. Adding to above CR and PR:

   CNS stable disease (SD) is achieving all the following:

   • < 50% reduction in the volumetric sum of all measurable (>/= 1 cm in LD) brain metastases compared to baseline
   • No progression on non-measurable lesions
   • No new CNS lesions (defined as any new lesion >/= 6 mm in LD)
   • Stable or decreasing steroid dose
   • No new/progressive tumor-related neurologic signs or symptoms
   • No progression of extra-CNS disease as assessed by RECIST

   CNS Progressive Disease (PD) was experiencing any of the following:

   ->/- 40% increase in the volumetric sum of all measurable (>/= 1 cm in LD) brain metastases compared to baseline

   • Progression on non-measurable lesions
   • New CNS lesions (defined as any new lesion >/= 6 mm in LD)
   • Increasing steroid dose
   • New/progressive tumor-related neurologic signs or symptoms
   • Progression of extra-CNS disease as assessed by RECIST
3. Site of First Progression [ Time Frame: Disease was evaluated radiologically at baseline and every 2 cycles on treatment. Off treatment, participants were followed every 3 months for progression and overall survival. Duration of follow-up for this study cohort approximated up to 3 years. ]
   Site of first progression was defined as progressive disease in either CNS or non-CNS sites by radiographic criteria.
4. Overall Survival [ Time Frame: Off treatment, participants were followed every 3 months for progression and overall survival. Duration of follow-up for this study cohort was up to 3 years. ]
   Overall survival is defined as the time from study entry to death or date last known alive and estimated using Kaplan-Meier (KM) methods.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Histologically or cytologically confirmed invasive breast cancer, with metastatic disease. patients without pathologic or cytologic confirmation of metastatic disease should have unequivocal evidence of metastasis by physical exam or radiologic study
• Measurable disease. Patients must have measurable CNS disease, defined as at least one parenchymal brain lesion that can be accurately measured in at least one dimension with longest dimension >/= 10mm by local radiology review
• New or progressive CNS lesions, as assessed by the patient's treating physician
• No increase in corticosteroid dose in the week prior to the baseline brain MRI
• 18 years of age or older
• Life expectancy of greater than 12 weeks
• ECOG performance status 0-2
• Normal organ and marrow function as outlined in the protocol
• Left ventricular ejection fraction >/= 50%, as determined by RVG or echocardiogram within 60 days prior to initiation of protocol therapy
• Prior carboplatin is allowed if it was not given in conjunction with bevacizumab
• Prior trastuzumab is allowed
• No prior bevacizumab since diagnosis of CNS metastases or within 6 months prior to diagnosis of CNS metastases
• Women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation

Exclusion Criteria:

• Patients who have had chemotherapy within 14 days prior to entering the study, or those who have not recovered adequately from adverse events due to agents administered earlier
• Patients may not receive any concurrent investigational agents while on study
• Patients may not receive any cancer-directed concurrent therapy , such as concurrent chemotherapy, radiotherapy, or hormonal therapy while on study. Concurrent treatment with bisphosphonates is allowed
• History of Grade 3 or 4 allergic reactions attributed to compounds of similar or identical biologic composition to bevacizumab, carboplatin, or trastuzumab
• Known contraindication to MRI with gadolinium contrast, such as cardiac pacemaker, shrapnel, or ocular foreign body
• Leptomeningeal carcinomatosis as the only site of CNS involvement
• More than 2 seizures over last 4 weeks prior to study entry
• Grade 1 or higher CNS hemorrhage on baseline brain MRI
• History of grade 2 or higher CNS hemorrhage within 12 months of study entry
• Inadequately controlled hypertension
• Prior history of hypertensive crisis or hypertensive encephalopathy
• NYHA Grade II or greater congestive heart failure
• History of myocardial infraction or unstable angina within 6 months prior to day 1
• Significant vascular disease within 6 months prior to day 1
• History of hemoptysis within 1 month prior to day 1
• Evidence of bleeding diathesis or significant coagulopathy
• Current, ongoing treatment with full-dose warfarin or its equivalent
• Use of aspirin (>325 mg/day) within 10 days prior to day 1
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to day 1 or anticipation of need for major surgical procedure during the course of the study.
• Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to day 1
• History of abdominal fistula or gastrointestinal perforation within 6 months prior to day 1
• Serious, non-healing wound, active ulcer, or untreated bone fracture
• Proteinuria as demonstrated by a UPC ration >/= 1.0 at screening
• Known hypersensitivity to any component of bevacizumab
• Pregnancy or lactation

Contacts and Locations

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Locations

United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02115
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02215

Sponsors and Collaborators

Dana-Farber Cancer Institute

Brigham and Women's Hospital

Massachusetts General Hospital

Beth Israel Deaconess Medical Center

Genentech, Inc.

Investigators

Principal Investigator:	Nancy Lin, MD	Dana-Farber Cancer Institute

More Information

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Responsible Party:	Nancy Lin, MD, Assistant Professor of Medicine, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier:	NCT01004172 History of Changes
Other Study ID Numbers:	09-224
First Posted:	October 29, 2009
Results First Posted:	May 22, 2017
Last Update Posted:	November 6, 2017
Last Verified:	October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Keywords provided by Nancy Lin, MD, Dana-Farber Cancer Institute:

carboplatin; bevacizumab

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Bevacizumab; Carboplatin	Trastuzumab; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Physiological Effects of Drugs; Growth Inhibitors; Antineoplastic Agents