Ignite Creation Date:
2024-05-06 @ 10:12 AM
Last Modification Date:
2024-10-26 @ 12:26 PM
Study NCT ID:
NCT03190967
Status:
TERMINATED
Last Update Posted:
2023-10-11
First Post:
2017-06-16
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:
National Institutes of Health Clinical Center CC
Study Overview
Official Title:
Phase III 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 andor 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 andor 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 III 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 36 mgkg intravenous IV every 21 days plus TMZ 30 40 or 50 mgm2 daily
Phase II T-DM1 36 mgkg versus T-DM1 36mgkg plus TMZ at recommended phase 2 dose RP2D
Phase I will follow a standard 33 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 andor 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 andor 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 III 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 36 mgkg intravenous IV every 21 days plus TMZ 30 40 or 50 mgm2 daily
Phase II T-DM1 36 mgkg versus T-DM1 36mgkg plus TMZ at recommended phase 2 dose RP2D
Phase I will follow a standard 33 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:
None
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?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 17-C-0115 | None | None | None |