BBBD Followed By Methotrexate and Carboplatin With or Without Trastuzumab in Treating Women With Breast Cancer That Has Spread to the Brain

NCT00397501 | Withdrawn Phase 1 DMC

• 4 other identifiers: IRB000021882188SOL-06015OHSU-2188
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

RATIONALE: Osmotic blood-brain barrier disruption uses certain drugs, such as mannitol, to open the blood vessels around the brain and allow tumor-killing substances to be carried directly to the brain. Drugs used in chemotherapy, such as methotrexate and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. 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. Trastuzumab may also help methotrexate and carboplatin work better by making tumor cells more sensitive to the drugs. Giving osmotic blood-brain barrier disruption together with methotrexate, carboplatin, and trastuzumab may kill more tumor cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of carboplatin when given together with methotrexate and trastuzumab after mannitol in treating women with breast cancer that has spread to the brain.

Conditions

Brain and Central Nervous System Tumors; Breast Cancer; Cognitive/Functional Effects; Drug/Agent Toxicity by Tissue/Organ; Psychosocial Effects of Cancer and Its Treatment

Keywords

cognitive/functional effects; psychosocial effects of cancer and its treatment; drug/agent toxicity by tissue/organ; recurrent breast cancer; stage IV breast cancer; adult tumors metastatic to brain

Outcome Measures

Primary Outcomes (2)

• Overall survival exceeding 5 months in patients with Human Epidermal growth factor Receptor 2(HER2)-negative disease

  1 year after initiation of treatment

• Overall survival exceeding 5 months in patients with HER2-positive disease

  1 year after initiation of treatment

Secondary Outcomes (5)

• Overall survival

  5 years after intitiation of treatment

• Progression-free survival

  5 years

• Complete response rate

  5 years

• Time to best response

  5 years

• Quality of life

  5 years

Study Arms (2)

HER-2 positive subjects

ACTIVE COMPARATOR

HER-2 positive subjects treated with trastuzumab

Biological: trastuzumab; Drug: carboplatin; Drug: methotrexate; Drug: sodium thiosulfate

HER-2 negative subjects

ACTIVE COMPARATOR

HER-2 negative subjects not treated with trastuzumab

Drug: carboplatin; Drug: methotrexate; Drug: sodium thiosulfate

Interventions

trastuzumab BIOLOGICAL

Trastuzamab, 6mg/kg, within 48 hrs before BBBD Then, Trastuzumab, 2mg/kg, weekly until next BBBD Then continue for 12 cycles

Also known as: Herceptin

HER-2 positive subjects

carboplatin DRUG

200mg/m2/day x 2 days; total dose 400mg/m2 Infused i.a. over 10 mins in 200ml of normal saline after MTX infusion

Also known as: carbo

HER-2 negative subjects; HER-2 positive subjects

methotrexate DRUG

2500 mg/day x 2 days; total dose 5000mg Infused over 10mins in 200ml saline beginning immediately after mannitol infusion

Also known as: MTX

HER-2 negative subjects; HER-2 positive subjects

sodium thiosulfate DRUG

STS dose admin i.v. over 15mins @ 4hrs post carboplatin = 20gm/m2; STS dose admin i.v. over 15mins @ 8hrs post carboplatin = 16gm/m2

Also known as: STS

HER-2 negative subjects; HER-2 positive subjects

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

DISEASE CHARACTERISTICS: * Histologically or cytologically confirmed breast cancer metastatic to the central nervous system (as documented by brain biopsy, cytology \[analysis from cerebrospinal fluid\]) OR radiographic evidence of brain metastasis with a diagnosis of systemic breast cancer * Patients must have stable or no systemic disease as determined by a CT scan of the chest, abdomen, and pelvis * HER2-positive or -negative disease by fluorescent in situ hybridization (FISH) or immunohistochemistry * Patients with HER2-positive disease and signs of intracranial herniation and/or spinal block may first undergo intraarterial chemotherapy off study (with carboplatin, methotrexate, and trastuzumab \[Herceptin®\] by the same routes used on study) until radiographically shown to be safe to undergo blood brain barrier disruption, at which point they may be enrolled in the study * Hormone receptor status not specified PATIENT CHARACTERISTICS: * Female * Menopausal status not specified * ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100% * Life expectancy \> 6 weeks * Hematocrit ≥ 25% * WBC ≥ 2,500/mm³ * Absolute neutrophil count ≥ 1,200/mm³ * Platelet count ≥100,000/mm³ * Creatinine clearance ≥ 50 mL/min (eligible for full-dose methotrexate) (30-49 mL/min allowed for patients receiving reduced-dose methotrexate) * Bilirubin ≤ 2.0 times upper limit of normal * LVEF normal by echocardiogram or MUGA * Adequate pulmonary and cardiac function to tolerate general anesthesia as determined by physical examination and history * No New York Heart Association class III-IV heart disease * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * No known allergy to trastuzumab (HER2-positive patients), carboplatin, methotrexate, or sodium thiosulfate * No hepatitis B or C positivity * No uncontrolled intercurrent illness including, but not limited to, any of the following: * Ongoing or active infection (e.g., HIV) * Symptomatic congestive heart failure * Unstable angina pectoris * Cardiac arrhythmia * Psychiatric illness or social situations that would limit compliance with study requirements PRIOR CONCURRENT THERAPY: * Prior surgery or biopsy allowed * Prior chemotherapy and radiation therapy for metastatic breast cancer allowed * No radiation or cytotoxic chemotherapy within the past 4 weeks (except trastuzumab or hormone therapy that has been part of the patient's ongoing treatment \[e.g., aromatase inhibitors for estrogen receptor positive patients\]) * No noncytotoxic regimens (e.g., targeted oral agents) within the past 2 weeks * No investigational agents within the past 4 weeks * No other concurrent anticancer agents or therapies

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• OHSU Knight Cancer Institute: lead
• National Cancer Institute (NCI): collaborator

MeSH Terms

Conditions

Central Nervous System Neoplasms; Breast Neoplasms; Drug-Related Side Effects and Adverse Reactions; Brain Neoplasms

Interventions

Trastuzumab; Carboplatin; Methotrexate; sodium thiosulfate

Condition Hierarchy (Ancestors)

Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Nervous System Diseases; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Chemically-Induced Disorders; Brain Diseases; Central Nervous System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Coordination Complexes; Organic Chemicals; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Edward A. Neuwelt, MD

  OHSU Knight Cancer Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: November 8, 2006
• First Posted: November 9, 2006
• Study Start: October 1, 2013
• Primary Completion: October 1, 2013
• Study Completion: October 1, 2013
• Last Updated: April 21, 2017

Record last verified: 2017-04