Brain and Central Nervous System TumorsPhase 1/2NCT00397501
BBBD Followed By Methotrexate and Carboplatin With or Without Trastuzumab in Treating Women With Breast Cancer That Has Spread to the Brain
A Phase 1/2 study testing trastuzumab, carboplatin and methotrexate in people with Brain and Central Nervous System Tumors and Breast Cancer, run by OHSU Knight Cancer Institute.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 75 years, women only
- Conditions the study is for
- Brain and Central Nervous System Tumors, Breast Cancer, Cognitive/Functional Effects
- What is being tested?
- trastuzumab, carboplatin and methotrexate
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- No sites listed yet
- Study dates
- Oct 2013to Oct 2013
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- Women only
- No healthy volunteers
- Adult, Older adult
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
About this study
Official title: A Phase I/II Pilot Study of Patients With Brain Metastasis Secondary to Breast Cancer Treated With Methotrexate and Carboplatin in Conjunction With Blood-Brain Barrier Disruption, With Concurrent Trastuzumab in HER-2 Positive Patients
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.
Read the detailed description
OBJECTIVES:
Primary
- Determine the safety and toxicity associated with blood-brain barrier disruption comprising transfemoral mannitol followed by methotrexate and carboplatin with or without trastuzumab (Herceptin®) in women with brain metastasis secondary to breast cancer. (Phase I)
- Determine if overall survival exceeds 5 months in patients with Human Epidermal growth factor Receptor 2(HER2)-positive or HER2-negative disease treated with this regimen. (Phase II)
Secondary
- Determine the overall survival of these patients.
- Compare the event-free and overall survival, steroid use, response rates, and time to best response in patients with HER2-positive vs HER2-negative disease.
- Assess the quality of life of patients treated with this regimen.
- Assess the neuropsychological effects of this treatment regimen in these patients.
- Determine cerebrospinal fluid levels of trastuzumab before and after blood-brain barrier disruption.
OUTLINE: This is a multicenter, phase I, pilot, dose-finding study of carboplatin followed by a phase II, open-label study.
- Phase I: Patients undergo osmotic blood-brain barrier disruption (BBBD) comprising mannitol by transfemoral catheterization followed by methotrexate intra-arterially (IA) over 10 minutes and carboplatin IA over 10 minutes on days 1 and 2. Patients also receive sodium thiosulfate IV over 15 minutes at 4 and 8 hours after each dose of carboplatin; leucovorin calcium IV or orally every 6 hours on days 3-9; and pegfilgrastim subcutaneously (SC) on day 4 or filgrastim (G-CSF) SC beginning on day 4 and continuing until blood counts recover (7-10 days). Patients with HER-2 positive disease receive trastuzumab (Herceptin®) IV over 90 minutes within 48 hours prior to BBBD and then weekly for 3 weeks (between BBBD therapy sessions). Treatment repeats every 4 weeks for up to 12 months in the absence of disease progression or unacceptable toxicity.
Cohorts of 3-6 patients receive decreasing doses of carboplatin and/or methotrexate if the proposed dose is not well tolerated. Dose-limiting toxicity is defined as grade IV hematologic toxicity with delay in subsequent treatment courses for 4 weeks OR grade III/IV nonhematologic toxicity without recovery in 14 days during the course of treatment.
- Phase II: Patients undergo BBBD as in phase I and receive carboplatin and methotrexate at the doses determined in phase I. Patients also receive sodium thiosulfate, leucovorin calcium, and pegfilgrastim or G-CSF as in phase I. Patients with HER2-positive disease also receive trastuzumab as in phase I.
Neuropsychological assessment is performed at baseline, every 6 months during treatment, every 6 months for 1 year, and then annually thereafter. Quality of life is assessed at baseline, every 3 months during treatment, at the completion of study treatment, every 6 months for 1 year, and then annually thereafter.
After completion of study therapy, patients are followed periodically.
PROJECTED ACCRUAL: A total of 78 patients will be accrued for this study.
- 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
- Being tested
- trastuzumab, carboplatin, methotrexate, sodium thiosulfate
- 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
- Medical subject headings
- Central Nervous System Neoplasms, Breast Neoplasms, Drug-Related Side Effects and Adverse Reactions, Brain Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
trastuzumabBiological
Also called Herceptin
Trastuzamab, 6mg/kg, within 48 hrs before BBBD
Then, Trastuzumab, 2mg/kg, weekly until next BBBD Then continue for 12 cycles
carboplatinDrug
Also called carbo
200mg/m2/day x 2 days; total dose 400mg/m2 Infused i.a. over 10 mins in 200ml of normal saline after MTX infusion
methotrexateDrug
Also called MTX
2500 mg/day x 2 days; total dose 5000mg Infused over 10mins in 200ml saline beginning immediately after mannitol infusion
sodium thiosulfateDrug
Also called STS
STS dose admin i.v. over 15mins @ 4hrs post carboplatin = 20gm/m2; STS dose admin i.v. over 15mins @ 8hrs post carboplatin = 16gm/m2
| Study group | Role | What they receive |
|---|---|---|
| HER-2 positive subjects | Active comparator | HER-2 positive subjects treated with trastuzumab Receives: Biological: trastuzumab; Drug: carboplatin; Drug: methotrexate; Drug: sodium thiosulfate |
| HER-2 negative subjects | Active comparator | HER-2 negative subjects not treated with trastuzumab Receives: Drug: carboplatin; Drug: methotrexate; Drug: sodium thiosulfate |
What is being measured
The primary outcome is the main question the study is designed to answer.
Overall survival exceeding 5 months in patients with Human Epidermal growth factor Receptor 2(HER2)-negative disease
Measured: 1 year after initiation of treatment
Overall survival exceeding 5 months in patients with HER2-positive disease
Measured: 1 year after initiation of treatment
Secondary outcomes (5)
Overall survival
Measured: 5 years after intitiation of treatment
Progression-free survival
Measured: 5 years
Complete response rate
Measured: 5 years
Time to best response
Measured: 5 years
Quality of life
Measured: 5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Nov 2006 (estimated)
- Study startOct 2013
- Primary completionOct 2013 (estimated)
- Study completionOct 2013 (estimated)
Why it stopped: after original approval, IRB closed enrollment; major revisions required to re-open.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Brain and Central Nervous System TumorsStudies of the same condition, open and under way.
- More trials run by OHSU Knight Cancer InstituteThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- OHSU Knight Cancer Institute
- Sponsor type
- University, hospital or other
- Collaborators
- National Cancer Institute (NCI)
- Responsible party
- Principal investigator, Edward Neuwelt, OHSU Knight Cancer Institute
- Investigators
- Edward A. Neuwelt, MD, Principal investigator, OHSU Knight Cancer Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00397501
- Sponsor's protocol ID
- IRB00002188
- Other IDs
- 2188, SOL-06015, OHSU-2188
- Status last verified
- Apr 2017
- First submitted
- 8 Nov 2006
- Last updated
- 21 Apr 2017
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 21 Apr 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I/II Pilot Study of Patients With Brain Metastasis Secondary to Breast Cancer Treated With Methotrexate and Carboplatin in Conjunction With Blood-Brain Barrier Disruption, With Concurrent Trastuzumab in HER-2 Positive Patients
- ClinicalTrials.gov ID
- NCT00397501
- Acronym / sponsor ID
- IRB00002188
- 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
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: after original approval, IRB closed enrollment; major revisions required to re-open.
- Enrolment
- 0 participants (actual)
- Lead sponsor
- OHSU Knight Cancer InstituteUniversity, hospital or other
- Collaborators
- National Cancer Institute (NCI)
- Study start
- Oct 2013
- Primary completion
- Oct 2013 (estimated)
- Study completion
- Oct 2013 (estimated)
- First posted
- 9 Nov 2006 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
OBJECTIVES:
Primary
- Determine the safety and toxicity associated with blood-brain barrier disruption comprising transfemoral mannitol followed by methotrexate and carboplatin with or without trastuzumab (Herceptin®) in women with brain metastasis secondary to breast cancer. (Phase I)
- Determine if overall survival exceeds 5 months in patients with Human Epidermal growth factor Receptor 2(HER2)-positive or HER2-negative disease treated with this regimen. (Phase II)
Secondary
- Determine the overall survival of these patients.
- Compare the event-free and overall survival, steroid use, response rates, and time to best response in patients with HER2-positive vs HER2-negative disease.
- Assess the quality of life of patients treated with this regimen.
- Assess the neuropsychological effects of this treatment regimen in these patients.
- Determine cerebrospinal fluid levels of trastuzumab before and after blood-brain barrier disruption.
OUTLINE: This is a multicenter, phase I, pilot, dose-finding study of carboplatin followed by a phase II, open-label study.
- Phase I: Patients undergo osmotic blood-brain barrier disruption (BBBD) comprising mannitol by transfemoral catheterization followed by methotrexate intra-arterially (IA) over 10 minutes and carboplatin IA over 10 minutes on days 1 and 2. Patients also receive sodium thiosulfate IV over 15 minutes at 4 and 8 hours after each dose of carboplatin; leucovorin calcium IV or orally every 6 hours on days 3-9; and pegfilgrastim subcutaneously (SC) on day 4 or filgrastim (G-CSF) SC beginning on day 4 and continuing until blood counts recover (7-10 days). Patients with HER-2 positive disease receive trastuzumab (Herceptin®) IV over 90 minutes within 48 hours prior to BBBD and then weekly for 3 weeks (between BBBD therapy sessions). Treatment repeats every 4 weeks for up to 12 months in the absence of disease progression or unacceptable toxicity.
Cohorts of 3-6 patients receive decreasing doses of carboplatin and/or methotrexate if the proposed dose is not well tolerated. Dose-limiting toxicity is defined as grade IV hematologic toxicity with delay in subsequent treatment courses for 4 weeks OR grade III/IV nonhematologic toxicity without recovery in 14 days during the course of treatment.
- Phase II: Patients undergo BBBD as in phase I and receive carboplatin and methotrexate at the doses determined in phase I. Patients also receive sodium thiosulfate, leucovorin calcium, and pegfilgrastim or G-CSF as in phase I. Patients with HER2-positive disease also receive trastuzumab as in phase I.
Neuropsychological assessment is performed at baseline, every 6 months during treatment, every 6 months for 1 year, and then annually thereafter. Quality of life is assessed at baseline, every 3 months during treatment, at the completion of study treatment, every 6 months for 1 year, and then annually thereafter.
After completion of study therapy, patients are followed periodically.
PROJECTED ACCRUAL: A total of 78 patients will be accrued for this study.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| HER-2 positive subjects | Active comparator | Biological: trastuzumab, Drug: carboplatin, Drug: methotrexate, Drug: sodium thiosulfateHER-2 positive subjects treated with trastuzumab |
| HER-2 negative subjects | Active comparator | Drug: carboplatin, Drug: methotrexate, Drug: sodium thiosulfateHER-2 negative subjects not treated with trastuzumab |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| trastuzumabAlso: HerceptinTrastuzamab, 6mg/kg, within 48 hrs before BBBD Then, Trastuzumab, 2mg/kg, weekly until next BBBD Then continue for 12 cycles | Biological | HER-2 positive subjects |
| carboplatinAlso: carbo200mg/m2/day x 2 days; total dose 400mg/m2 Infused i.a. over 10 mins in 200ml of normal saline after MTX infusion | Drug | HER-2 negative subjects, HER-2 positive subjects |
| methotrexateAlso: MTX2500 mg/day x 2 days; total dose 5000mg Infused over 10mins in 200ml saline beginning immediately after mannitol infusion | Drug | HER-2 negative subjects, HER-2 positive subjects |
| sodium thiosulfateAlso: STSSTS dose admin i.v. over 15mins @ 4hrs post carboplatin = 20gm/m2; STS dose admin i.v. over 15mins @ 8hrs post carboplatin = 16gm/m2 | Drug | HER-2 negative subjects, HER-2 positive subjects |
Primary outcome
Overall survival exceeding 5 months in patients with Human Epidermal growth factor Receptor 2(HER2)-negative disease
Time frame: 1 year after initiation of treatment
Overall survival exceeding 5 months in patients with HER2-positive disease
Time frame: 1 year after initiation of treatment
5 secondary outcomes
Overall survival
Time frame: 5 years after intitiation of treatment
Progression-free survival
Time frame: 5 years
Complete response rate
Time frame: 5 years
Time to best response
Time frame: 5 years
Quality of life
Time frame: 5 years
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Apr 2017.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Edward A. Neuwelt, MD principal investigator
OHSU Knight Cancer Institute
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing trastuzumab, carboplatin and methotrexate in people with Brain and Central Nervous System Tumors and Breast Cancer, run by OHSU Knight Cancer Institute.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 21 Apr 2017. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Overall survival exceeding 5 months in patients with Human Epidermal growth factor Receptor 2(HER2)-negative disease (time frame: 1 year after initiation of treatment). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Apr 2017.