Chemotherapeutic Agents in Brain/Breast

July 31, 2013 updated by: Case Comprehensive Cancer Center

Clinical Study to Assess Entry of Chemotherapeutic Agents Into Brain Metastases in Women With Breast Cancer

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Lapatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Studying samples of tumor tissue and blood from patients may help doctors understand how well these drugs can be carried to the brain.

PURPOSE: More definitive knowledge of the penetration of chemotherapeutic and other agents into the brain is necessary for the future rational design of drug and drug regimens that target brain metastases. This clinical trial is studying how well capecitabine, cyclophosphamide, doxorubicin, gemcitabine, lapatinib, paclitaxel, trastuzumab, or vinorelbine penetrates brain tumors.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

OBJECTIVES:

To determine the concentration of capecitabine, cyclophosphamide, doxorubicin hydrochloride, gemcitabine hydrochloride, lapatinib ditosylate, paclitaxel, trastuzumab (Herceptin®), or vinorelbine ditartrate in brain metastases in women with breast cancer.
To analyze drug penetrability by modeling the relationship between drug concentration in the tumor and drug concentration in blood samples.

OUTLINE: Patients are assigned to receive 1 of the 8 agents by the patient's treating oncologist.

Patients receive a single dose of the following study drugs immediately preceding surgery: oral capecitabine; cyclophosphamide IV over 30 minutes; doxorubicin hydrochloride IV over 15 minutes; gemcitabine hydrochloride IV over 30 minutes; oral lapatinib ditosylate*; paclitaxel IV over 3 hours; trastuzumab (Herceptin®) IV over 30-90 minutes; or vinorelbine ditartrate IV over 10-30 minutes . Patients then undergo craniotomy for resection of the brain metastases.

NOTE: *Patients receive oral lapatinib ditosylate at least 3 days prior to surgery and immediately before surgery.

All patients receiving cyclophosphamide, doxorubicin hydrochloride, gemcitabine hydrochloride, paclitaxel, or vinorelbine ditartrate also receive a single dose of pegfilgrastim subcutaneously (SC) 24-48 hours after the study drug administration OR filgrastim (G-CSF) SC once daily for 10 days, beginning 24-48 hours after the study drug administration.

Blood samples are collected periodically for pharmacological studies. Tissue samples obtained at surgical resection and blood samples are used to establish cell lines and analyzed for drug concentration by HPLC, LC-MS/MS or ELISA.

Study Type

Observational

Enrollment (Actual)

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

United States
- New York
  - New York, New York, United States, 10065
    - Memorial Sloan Kettering
- Ohio
  - Cleveland, Ohio, United States, 44195
    - Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

Genders Eligible for Study

Female

Sampling Method

Non-Probability Sample

Study Population

Patients will be recruited from a population of breast cancer patients who are to undergo clinically indicated surgical resection of one of more symptomatic brain metastasis(es) treated at the investigational centers.

Description

DISEASE CHARACTERISTICS:

Histologically or cytologically confirmed breast carcinoma with ≥ 1 suspected or known parenchymal brain metastases for which surgical resection or biopsy is clinically indicated
Treating oncologist must agree that the patient would derive clinical benefit from receiving ≥ 1 of the following study agents:
- Capecitabine, cyclophosphamide, doxorubicin hydrochloride, gemcitabine hydrochloride, lapatinib ditosylate, paclitaxel, trastuzumab (Herceptin®), or vinorelbine ditartrate
Hormone receptor status not specified

PATIENT CHARACTERISTICS:

Menopausal status not specified
Karnofsky performance status 50-100%
Life expectancy ≥ 3 months
Absolute granulocyte count ≥ 1,500/mm³
Platelet count ≥ 100,000/mm³
Hemoglobin ≥ 10 g/dL
Creatinine ≤ 1.5 times upper limit of normal (ULN)
Bilirubin (total) ≤ 1.5 times ULN
AST ≤ 3 times ULN
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception during and for three months after completion of study treatment
No severe NYHA class III-IV cardiac insufficiency with uncontrolled and/or unstable cardiac or coronary artery disease
No history of noncompliance to medical regimens or inability or unwillingness to return for all scheduled visits

PRIOR CONCURRENT THERAPY:

No toxicity > grade 2 from prior chemotherapy or radiotherapy remains at the time of study entry
At least 60 days since prior bevacizumab
At least 4 weeks since prior cranial radiotherapy
At least 3 weeks since prior cytotoxic chemotherapy (6 weeks for nitrosoureas or mitomycin C)
At least 2 weeks since prior non-cytotoxic drugs (e.g., small molecule-targeted drugs)
No concurrent experimental therapies
Concurrent hormone therapy and/or trastuzumab (Herceptin®) allowed

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concentration of drug Time Frame: Post-Op Per Sample Collection	Serum/plasma concentrations: measured for all agents except trastuzumab by HPLC or LC-MS/MS. Trastuzumab concentrations measured by enzyme linked immunosorbent assay. Compared to tissue levels and the extent of change in serum/plasma during the surgical process will be noted. Tissue Concentrations: determined by HPLC/LC-MS/MS or by ELISA. The objective would be to compare tumor concentration to brain adjacent to tumor, which often has an intact BBB. The degree of BBB compromise in the specimens will be assessed through analysis of serum protein levels and hemoglobin.	Post-Op Per Sample Collection

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Case Comprehensive Cancer Center

Collaborators

National Cancer Institute (NCI)

United States Department of Defense

Investigators

Principal Investigator: David M. Peereboom, MD, Case Comprehensive Cancer Center
Principal Investigator: Robert Weil, MD, The Cleveland Clinic

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Morikawa A, Peereboom DM, Thorsheim HR, Samala R, Balyan R, Murphy CG, Lockman PR, Simmons A, Weil RJ, Tabar V, Steeg PS, Smith QR, Seidman AD. Capecitabine and lapatinib uptake in surgically resected brain metastases from metastatic breast cancer patients: a prospective study. Neuro Oncol. 2015 Feb;17(2):289-95. doi: 10.1093/neuonc/nou141. Epub 2014 Jul 11. Erratum In: Neuro Oncol. 2015 Oct;17(10):1423.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2008

Primary Completion (ACTUAL)

April 1, 2013

Study Completion (ACTUAL)

April 1, 2013

Study Registration Dates

First Submitted

November 20, 2008

First Submitted That Met QC Criteria