Ignite Creation Date:
2025-12-25 @ 12:38 AM
Ignite Modification Date:
2026-01-03 @ 10:20 AM
Study NCT ID:
NCT03190967
Status:
TERMINATED
Last Update Posted:
2023-10-11
First Post:
2017-06-16
Is NOT Gene Therapy:
True
Has Adverse Events:
True
Brief Title:
T-DM1 Alone Versus T-DM1 and Metronomic Temozolomide in Secondary Prevention of HER2-Positive Breast Cancer Brain Metastases Following Stereotactic Radiosurgery
Sponsor:
National Cancer Institute (NCI)
Organization:
Study Overview
Official Title:
Phase I/II Study of T-DM1 Alone Versus T-DM1 and Metronomic Temozolomide in Secondary Prevention of HER2-Positive Breast Cancer Brain Metastases Following Stereotactic Radiosurgery
Status:
TERMINATED
Status Verified Date:
2023-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
The phase II portion was never started as we could no longer get the drug from the manufacturer.
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Background:
Sometimes breast cancer spreads (metastasizes) to the brain. Researchers want to study new treatments for brain metastases. The drug Temozolomide is approved to treat brain tumors. Researchers want to see if combining it with the drug trastuzumab emtansine (T-DMI) prevents the formation of new metastases in the brain.
Objective:
To study if Temozolomide with T-DM1 lowers the chance of having new metastases in the brain.
Eligibility:
Adults at least 18 years old with a human epidermal growth factor receptor 2 (HER2)-positive breast cancer that has spread to the brain and was recently treated with stereotactic radiation or surgery.
Design:
Participants will be screened with
* Medical history
* Physical exam
* Heart tests
* A scan (computed tomography (CT) that makes a picture of the body using a small amount of radiation
* A scan (magnetic resonance imaging (MRI) that uses a magnetic field to make an image of the brain
* Blood tests.
* Pregnancy test.
The study will be done in 3-week cycles.
All participants will get T-DM1 on Day 1 of every cycle through a small plastic tube inserted in an arm vein.
Some participants will also take Temozolomide capsules by mouth every day.
Participants will keep a medication diary.
During the study, participants will also:
* Repeat most of the screening tests.
* Answer questions about their general well-being and functioning.
Participants will have lumbar puncture at least 2 times. A needle is inserted into the spinal canal low in the back and cerebrospinal fluid is collected. This will be done with local anesthesia and with the help of images.
Participants will be asked to provide tumor samples when available.
Participants will have a follow-up visit about 1 month after stopping the study drug. They will be contacted by telephone or email every 3 months after that.
Sometimes breast cancer spreads (metastasizes) to the brain. Researchers want to study new treatments for brain metastases. The drug Temozolomide is approved to treat brain tumors. Researchers want to see if combining it with the drug trastuzumab emtansine (T-DMI) prevents the formation of new metastases in the brain.
Objective:
To study if Temozolomide with T-DM1 lowers the chance of having new metastases in the brain.
Eligibility:
Adults at least 18 years old with a human epidermal growth factor receptor 2 (HER2)-positive breast cancer that has spread to the brain and was recently treated with stereotactic radiation or surgery.
Design:
Participants will be screened with
* Medical history
* Physical exam
* Heart tests
* A scan (computed tomography (CT) that makes a picture of the body using a small amount of radiation
* A scan (magnetic resonance imaging (MRI) that uses a magnetic field to make an image of the brain
* Blood tests.
* Pregnancy test.
The study will be done in 3-week cycles.
All participants will get T-DM1 on Day 1 of every cycle through a small plastic tube inserted in an arm vein.
Some participants will also take Temozolomide capsules by mouth every day.
Participants will keep a medication diary.
During the study, participants will also:
* Repeat most of the screening tests.
* Answer questions about their general well-being and functioning.
Participants will have lumbar puncture at least 2 times. A needle is inserted into the spinal canal low in the back and cerebrospinal fluid is collected. This will be done with local anesthesia and with the help of images.
Participants will be asked to provide tumor samples when available.
Participants will have a follow-up visit about 1 month after stopping the study drug. They will be contacted by telephone or email every 3 months after that.
Detailed Description:
Background:
* Breast cancer is the most common cancer in women. In the human epidermal growth factor receptor 2 (HER2+) subtype, brain metastases can occur in up to 25-40% of patients.
* The standard therapy for brain metastases continues to be surgery or stereotactic radiosurgery (SRS) and/or whole brain radiation therapy (WBRT).
* Currently, independently of localized or systemic treatment modality, once brain metastases are established, options for treatment are limited, and the disease almost invariably progresses, limiting not only survival but also quality of life in most patients.
* Preclinical literature suggests the hypothesis that preventing the formation of a metastasis by a drug may be more efficacious than attempting to shrink an established lesion.
* Our group has shown in vitro and in vivo in animal models injected with a brain tropic O6-methylguanine DNA methyltransferase (MGMT) + cell line, that even in very low doses temozolomide (TMZ) administered in a prophylactic, metronomic fashion can significantly prevent development of brain metastases.
* We propose a secondary-prevention clinical trial with oral TMZ given to HER2+ breast cancer patients with brain metastases after recent local treatment (SRS or surgical resection) in combination with the anti-HER2 agent T-DM1 for systemic control of disease.
Objectives:
* Phase I (run in): to identify the maximum tolerated dose (MTD) of TMZ when used in combination with T-DM1.
* Phase II: to determine if the combination regimen of trastuzumab emtansine (T-DM1) and temozolomide improves the freedom from distant new brain metastases following stereotactic radiosurgery or surgical resection in HER2-positive breast cancer brain metastases, as compared to T-DM1 alone guided by one-year results as an important benchmark for measuring improvement.
Eligibility:
Phase I:
* Histologically confirmed HER2+ breast cancer.
* Eastern Cooperative Oncology (ECOG) performance status 0-2 and adequate organ and marrow function.
* Brain metastases, treated within 12 weeks of study entry with SRS, resection or WBRT.
* Patients with leptomeningeal metastatic disease are ineligible.
* Patients that are unable to complete a brain MRI with contrast are ineligible.
* Patients with breast tissue expanders must have those removed before enrollment.
* Hepatitis B virus (HBV), hepatitis C virus (HCV) or human immunodeficiency virus (HIV)-positive patients are ineligible.
* Patient with impaired cardiac function or clinically significant cardiac disease are ineligible.
* Corticosteroids will be allowed at enrollment and during the first month of treatment with T-DM1 after SRS, up to a dose of no more than 10mg of dexamethasone daily or equivalent. Patients that need to continue corticosteroids after the initial month will not be allowed to increase the dose after that period and will be taken off protocol.
Phase II:
* Histologically confirmed HER2+ breast cancer.
* ECOG performance status 0-2 and adequate organ and marrow function.
* 1-10 brain metastases, by contrast MRI, treated within 12 weeks of study entry with SRS and/or resection.
* Patients with leptomeningeal metastatic disease are ineligible.
* Patients with history of WBRT are ineligible.
* Patients that are unable to complete a brain MRI with contrast are ineligible.
* Patients with breast tissue expanders must have those removed before enrollment.
* HBV, HCV or HIV-positive patients are ineligible.
* Patient with impaired cardiac function or clinically significant cardiac disease are ineligible.
* Corticosteroids will be allowed at enrollment and during the first month of treatment with T-DM1 after SRS, up to a dose of no more than 10mg of dexamethasone daily or equivalent. Patients that need to continue corticosteroids after the initial month will not be allowed to increase the dose after that period and will be taken off protocol.
Design:
* This is a Phase I/II open label study that will evaluate the potential benefit of TMZ in prevention of new brain metastases in patients with limited brain metastases from HER2+ breast cancer, previously treated with SRS or surgical resection of brain metastases.
* All patients will receive the standard second-line therapy for HER2+ metastatic breast cancer: T-DM1. During phase II patients will be randomized between T-DM1 plus TMZ versus T-DM1 alone.
* Phase I run in: T-DM1 3.6 mg/kg intravenous (IV) every 21 days plus TMZ 30, 40 or 50 mg/m\^2 daily.
* Phase II: T-DM1 3.6 mg/kg versus T-DM1 3.6mg/kg plus TMZ at recommended phase 2 dose (RP2D).
* Phase I will follow a standard 3+3 design. Thus, with 3 dose levels, up to 18 patients may be included in the initial safety evaluation.
* In the phase II portion of the trial, a total of 49 evaluable subjects per arm (98 total) will need to be randomized over a 3-year period and followed for an additional 2 years from the date of entry of the last patient, with occurrence of 79 total relapses in both arms combined, in order to have 80% power to compare the curves.
* Breast cancer is the most common cancer in women. In the human epidermal growth factor receptor 2 (HER2+) subtype, brain metastases can occur in up to 25-40% of patients.
* The standard therapy for brain metastases continues to be surgery or stereotactic radiosurgery (SRS) and/or whole brain radiation therapy (WBRT).
* Currently, independently of localized or systemic treatment modality, once brain metastases are established, options for treatment are limited, and the disease almost invariably progresses, limiting not only survival but also quality of life in most patients.
* Preclinical literature suggests the hypothesis that preventing the formation of a metastasis by a drug may be more efficacious than attempting to shrink an established lesion.
* Our group has shown in vitro and in vivo in animal models injected with a brain tropic O6-methylguanine DNA methyltransferase (MGMT) + cell line, that even in very low doses temozolomide (TMZ) administered in a prophylactic, metronomic fashion can significantly prevent development of brain metastases.
* We propose a secondary-prevention clinical trial with oral TMZ given to HER2+ breast cancer patients with brain metastases after recent local treatment (SRS or surgical resection) in combination with the anti-HER2 agent T-DM1 for systemic control of disease.
Objectives:
* Phase I (run in): to identify the maximum tolerated dose (MTD) of TMZ when used in combination with T-DM1.
* Phase II: to determine if the combination regimen of trastuzumab emtansine (T-DM1) and temozolomide improves the freedom from distant new brain metastases following stereotactic radiosurgery or surgical resection in HER2-positive breast cancer brain metastases, as compared to T-DM1 alone guided by one-year results as an important benchmark for measuring improvement.
Eligibility:
Phase I:
* Histologically confirmed HER2+ breast cancer.
* Eastern Cooperative Oncology (ECOG) performance status 0-2 and adequate organ and marrow function.
* Brain metastases, treated within 12 weeks of study entry with SRS, resection or WBRT.
* Patients with leptomeningeal metastatic disease are ineligible.
* Patients that are unable to complete a brain MRI with contrast are ineligible.
* Patients with breast tissue expanders must have those removed before enrollment.
* Hepatitis B virus (HBV), hepatitis C virus (HCV) or human immunodeficiency virus (HIV)-positive patients are ineligible.
* Patient with impaired cardiac function or clinically significant cardiac disease are ineligible.
* Corticosteroids will be allowed at enrollment and during the first month of treatment with T-DM1 after SRS, up to a dose of no more than 10mg of dexamethasone daily or equivalent. Patients that need to continue corticosteroids after the initial month will not be allowed to increase the dose after that period and will be taken off protocol.
Phase II:
* Histologically confirmed HER2+ breast cancer.
* ECOG performance status 0-2 and adequate organ and marrow function.
* 1-10 brain metastases, by contrast MRI, treated within 12 weeks of study entry with SRS and/or resection.
* Patients with leptomeningeal metastatic disease are ineligible.
* Patients with history of WBRT are ineligible.
* Patients that are unable to complete a brain MRI with contrast are ineligible.
* Patients with breast tissue expanders must have those removed before enrollment.
* HBV, HCV or HIV-positive patients are ineligible.
* Patient with impaired cardiac function or clinically significant cardiac disease are ineligible.
* Corticosteroids will be allowed at enrollment and during the first month of treatment with T-DM1 after SRS, up to a dose of no more than 10mg of dexamethasone daily or equivalent. Patients that need to continue corticosteroids after the initial month will not be allowed to increase the dose after that period and will be taken off protocol.
Design:
* This is a Phase I/II open label study that will evaluate the potential benefit of TMZ in prevention of new brain metastases in patients with limited brain metastases from HER2+ breast cancer, previously treated with SRS or surgical resection of brain metastases.
* All patients will receive the standard second-line therapy for HER2+ metastatic breast cancer: T-DM1. During phase II patients will be randomized between T-DM1 plus TMZ versus T-DM1 alone.
* Phase I run in: T-DM1 3.6 mg/kg intravenous (IV) every 21 days plus TMZ 30, 40 or 50 mg/m\^2 daily.
* Phase II: T-DM1 3.6 mg/kg versus T-DM1 3.6mg/kg plus TMZ at recommended phase 2 dose (RP2D).
* Phase I will follow a standard 3+3 design. Thus, with 3 dose levels, up to 18 patients may be included in the initial safety evaluation.
* In the phase II portion of the trial, a total of 49 evaluable subjects per arm (98 total) will need to be randomized over a 3-year period and followed for an additional 2 years from the date of entry of the last patient, with occurrence of 79 total relapses in both arms combined, in order to have 80% power to compare the curves.
Study Oversight
Has Oversight DMC:
True
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
Secondary ID Infos
| Secondary ID | Type | Domain | Link | View |
|---|---|---|---|---|
| 17-C-0115 | None | None | View |