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| ID | Type | Description | Link |
|---|---|---|---|
| STU00040150 | Other Identifier | Northwestern University IRB |
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The drug being studied is Trastuzumab, a medicine that is used to slow or stop the growth of cancerous tumors that are HER-2 positive. Patients are being asked to participate in this study because they have been diagnosed with having tumor cells in their spinal fluid. This study will investigate the safety and effects of this drug when given directly into the spinal fluid.
Phase I/II Dose Escalation Trial to Assess Safety of Intrathecal Trastuzumab for the Treatment of Leptomeningeal Metastases in HER2 Positive Breast Cancer The purpose of this research study is to determine a safe dose of the drug Trastuzumab and then determine how effective this treatment is.
Phase I: Patients will be treated in cohorts of 3-6 based on standard phase I dose escalation parameters requiring 0/3 or 1/6 patients per cohort to have a DLT before dose escalation. Dosing is as follows: Cohort 1-10 mg IT, cohort 2-20 mg IT, cohort 3-30 mg IT and cohort 4-40 mg IT. Patients will be treated twice a week for 4 weeks, then once a week for 4 weeks, and then every 2 weeks. Toxicity for DLT will be assessed during first 4 weeks of treatment. Phase II: Patients will be treated with the MTD or maximal defined dose. Patients will be treated twice a week for 4 weeks, then once a week for 4 weeks, and then every 2 weeks.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| intravenous trastuzumab infusions | Experimental | A Phase I single dose study (H0407g) of intravenous trastuzumab infusions ranging from 10-500 mg resulted in dose-dependent pharmacokinetics (PK) with serum clearance of trastuzumab decreasing with an increasing dose at doses <250 mg. PK modeling of trastuzumab concentration-time data from 7 patients that were administered doses of 250 mg and 500 mg had in a mean halflife of 5.8 days (range 1-32 days). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Trastuzumab | Radiation | Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks |
|
| Measure | Description | Time Frame |
|---|---|---|
| Number of Dose Limiting Toxicities (DLT) of IT Trastuzumab in Sequential Cohorts of Escalating Doses for Patients With Leptomeningeal Metastases in HER2+ Breast Cancer. | Patients will be treated using a standard 3+3 dose-escalation design for cohorts 1 and 2. This will be followed by an accelerated phase I for cohorts 3 and 4, and then a standard 3 + 3 for the 5th cohort. In the accelerated phase (cohorts 3 and 4), 1 patient will be enrolled per cohort; if a toxicity is seen in that patient then the cohort would be expanded to 6 patients to allow for 1/6 patients per cohort to have a dose limiting toxicity (DLT) before dose escalation. Cohort 5 will enroll a total of 6 patients regardless of the toxicity experienced in patient one. However, if 2 or more DLTs are observed in cohort 5, cohort 4 will be reopened to enroll of a total of 6 patients. Whatever dose is ultimately declared the MTD should have 6 patients total. If 1/6 DLTs are seen in cohort 5 that will be considered the MTD. Dosing is as follows: Cohort 1-10 mg IT Cohort 2-20 mg IT Cohort 3-40 mg IT Cohort 4-60 mg IT Cohort 5-80 mg IT | From treatment initiation through the first 4 weeks of treatment. |
| Best Response to IT Trastuzumab: Radiological, Cytological and Clinical in Treatment With Intrathecal Trastuzumab for Patients With Leptomeningeal Metastases in HER2+ Breast Cancer. | Best response will be assessed using a combination CSF cytology assessment, radiographic assessment and clinical function assessments. Best response will be defined as the best response seen during treatment as compared to baseline that is confirmed on subsequent response assessment. | Baseline then at 4 weeks, 8 weeks and then every 8 weeks +/- 3 days, until disease progression or toxicity,range of cycles completed 1-22 cycles where 1 cycle = 28 days. |
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| Measure | Description | Time Frame |
|---|---|---|
| Define the CSF PK of IT Trastuzumab. | Patients may need a CSF flow study at the discretion of the treating principal investigator. If a spinal block is seen by CSF flow study or MRI, it will need local RT prior to treatment. Concurrent radiation is not allowed. | CSF analysis for cytology will be done every 2 weeks when CSF is obtained for PK and then every 4 weeks |
Inclusion Criteria:
ELIGIBILITY CRITERIA
HER2 positive (IHC 3+ and/or FISH positive) breast cancer patients with leptomeningeal metastases by MRI or CSF (if MRI is negative).
o Review will be performed for cases not reviewed at Northwestern for confirmation, but will not preclude patients from entering the trial (pathology report is sufficient for registration).
Patients can have concomitant brain metastases as long as they do not require active treatment or have been treated.
Patients with leptomeningeal disease from ependymomas, gliomas, and medulloblastoma will be eligible for phase I
Life expectancy > 8 weeks
Normal renal (creatinine < 1.5 ULN), liver (bilirubin < 1.5 x ULN, transaminases < 3.0 x ULN, except in known hepatic metastasis, wherein may be < 5 x ULN) and blood counts (WBC > 3.0, Neutrophils > 1500, platelets >100 000, Hemoglobin > 10).
LVEF > 50%
KPS > 50
Age > 18 years
Cannot be on systemic agents (chemotherapy) that have CNS penetration unless they develop leptomeningeal metastases while on these agent(s) and have controlled systemic disease. May continue on IV trastuzumab, lapatinib or hormonal agents if controlling systemic disease and developed LM while on therapy. Patients requiring systemic chemotherapy are eligible but will not be able to start treatment until after the first assessment by imaging and cytology.
Patients may need a CSF flow study at the discretion of the treating principal investigator. If a spinal block is seen by CSF flow study or MRI, it will need local RT prior to treatment. Concurrent radiation is not allowed.
Patients should be > 2 weeks from RT treatment and all effects of treatment should have resolved
No limit on prior systemic or IT therapies.
CSF sampling to document LM if not documented on MRI.
Must be willing to have an Ommaya reservoir placed.
NO history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix) unless in complete remission and off all therapy for the disease for a minimum of 3 years.
Significant medical or psychiatric illness that would interfere with compliance and ability to tolerate treatment as outlined in the protocol.
Women of childbearing potential and sexually active males must commit to the use of effective contraception while on study.
Women may not be pregnant or breast-feeding.
Ability to sign an informed consent; can be signed by family member or health care proxy. Informed consent must be done prior to registration on study.
All patients must have given signed, informed consent prior to registration on study.
No known hypersensitivity to trial medications Note: The eligibility criteria listed above are interpreted literally and cannot be waived.
Exclusion Criteria:
- Any deviations from the inclusion criteria
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| Name | Affiliation | Role |
|---|---|---|
| Jeffrey Raizer, MD | Northwestern University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of California San Francisco (UCSF) | San Francisco | California | 94143-1710 | United States | ||
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32506369 | Derived | Malani R, Fleisher M, Kumthekar P, Lin X, Omuro A, Groves MD, Lin NU, Melisko M, Lassman AB, Jeyapalan S, Seidman A, Skakodub A, Boire A, DeAngelis LM, Rosenblum M, Raizer J, Pentsova E. Cerebrospinal fluid circulating tumor cells as a quantifiable measurement of leptomeningeal metastases in patients with HER2 positive cancer. J Neurooncol. 2020 Jul;148(3):599-606. doi: 10.1007/s11060-020-03555-z. Epub 2020 Jun 6. |
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The study opened for accrual on April 26, 2011 with first patient being treated August 1, 2011, with an accrual goal of up to 48 patients for phase I/II combined. Amendment 5 added 5th cohort to allow higher dose. The study was suspended April 12, 2014 and reopened on August 28, 2014 for phase II. The study closed to accrual June 2, 2016.
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| ID | Title | Description |
|---|---|---|
| FG000 | Cohort 1 - Trastuzumab 10mg IT 2/Week | Intrathecal Trastuzumab 10 mg IT will be administered in Cohort 1 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days. |
| FG001 | Cohort 2 - Trastuzumab 20mg IT 2/Week | Intrathecal Trastuzumab 20 mg IT will be administered in Cohort 2 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days. |
| FG002 | Cohort 3- Trastuzumab 40mg IT 2/Week | Intrathecal Trastuzumab 40 mg IT will be administered in Cohort 3 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days. |
| FG003 | Cohort 4 - Trastuzumab 60mg IT 2/Week | Intrathecal Trastuzumab 60 mg IT will be administered in Cohort 4 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days. |
| FG004 | Cohort 5 - 80mg IT 2/Week | Intrathecal Trastuzumab 80 mg IT will be administered in Cohort 5 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days. |
| FG005 | Phase II - Transtuzumab 80mg IT 2/Week | Intrathecal Trastuzumab 10 mg IT will be administered in phase II portion of the study. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Completed 4 Weeks/1 Cycle of Treatment |
|
| ||||||||||||||||||
| Completed 8 Weeks/2 Cycles of Treatment |
| |||||||||||||||||||
| Started 9th Week/Cycle 3 of Treatment |
| |||||||||||||||||||
| Follow-up Every 3 Months Until Death |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Cohort 1 - Trastuzumab 10mg IT 2/Week | Intrathecal Trastuzumab 10 mg IT will be administered in Cohort 1 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days. |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Dose Limiting Toxicities (DLT) of IT Trastuzumab in Sequential Cohorts of Escalating Doses for Patients With Leptomeningeal Metastases in HER2+ Breast Cancer. | Patients will be treated using a standard 3+3 dose-escalation design for cohorts 1 and 2. This will be followed by an accelerated phase I for cohorts 3 and 4, and then a standard 3 + 3 for the 5th cohort. In the accelerated phase (cohorts 3 and 4), 1 patient will be enrolled per cohort; if a toxicity is seen in that patient then the cohort would be expanded to 6 patients to allow for 1/6 patients per cohort to have a dose limiting toxicity (DLT) before dose escalation. Cohort 5 will enroll a total of 6 patients regardless of the toxicity experienced in patient one. However, if 2 or more DLTs are observed in cohort 5, cohort 4 will be reopened to enroll of a total of 6 patients. Whatever dose is ultimately declared the MTD should have 6 patients total. If 1/6 DLTs are seen in cohort 5 that will be considered the MTD. Dosing is as follows: Cohort 1-10 mg IT Cohort 2-20 mg IT Cohort 3-40 mg IT Cohort 4-60 mg IT Cohort 5-80 mg IT | Posted | Number | DLTs | From treatment initiation through the first 4 weeks of treatment. |
|
Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Cohort 1 - Trastuzumab 10mg IT 2/Week | Intrathecal Trastuzumab 10 mg IT will be administered in Cohort 1 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Pericardial effusion | Cardiac disorders | CTCAE (4.03) | Systematic Assessment | Patient also experienced venous thromboembolism during inpatient hospitalization. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anemia | Blood and lymphatic system disorders | CTCAE (4.03) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Jeffrey Raizer, MD | Northwestern University | Jeffrey.Raizer@nm.org |
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| ID | Term |
|---|---|
| D001943 | Breast Neoplasms |
| ID | Term |
|---|---|
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D001941 | Breast Diseases |
| D012871 | Skin Diseases |
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| ID | Term |
|---|---|
| D000068878 | Trastuzumab |
| ID | Term |
|---|---|
| D061067 | Antibodies, Monoclonal, Humanized |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
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|
| Northwestern University |
| Chicago |
| Illinois |
| 60611 |
| United States |
| Tufts Medical Center | Boston | Massachusetts | 02111 | United States |
| Dana Farber Cancer Institute | Boston | Massachusetts | 02215 | United States |
| Columbia University | New York | New York | 10032 | United States |
| Memorial Sloan-Kettering Cancer Center | New York | New York | 10065 | United States |
| Rhode Island Hospital | Providence | Rhode Island | 02903 | United States |
| Texas Oncology-Austin | Austin | Texas | 78705 | United States |
| COMPLETED |
|
| NOT COMPLETED |
|
|
| COMPLETED |
|
| NOT COMPLETED |
|
|
| COMPLETED |
|
| NOT COMPLETED |
|
|
| Cohort 2 - Trastuzumab 20mg IT 2/Week |
Intrathecal Trastuzumab 20 mg IT will be administered in Cohort 2 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days. |
| BG002 | Cohort 3- Trastuzumab 40mg IT 2/Week | Intrathecal Trastuzumab 40 mg IT will be administered in Cohort 3 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days. |
| BG003 | Cohort 4 - Trastuzumab 60mg IT 2/Week | Intrathecal Trastuzumab 60 mg IT will be administered in Cohort 4 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days. |
| BG004 | Cohort 5 - 80mg IT 2/Week | Intrathecal Trastuzumab 80 mg IT will be administered in Cohort 5 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days. |
| BG005 | Phase II - Transtuzumab 80mg IT 2/Week | Intrathecal Trastuzumab 10 mg IT will be administered in phase II portion of the study. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days. |
| BG006 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| Description |
|---|
| OG000 | Cohort 1 - Trastuzumab 10mg IT 2/Week | Intrathecal Trastuzumab 10 mg IT will be administered in Cohort 1 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days. |
| OG001 | Cohort 2 - Trastuzumab 20mg IT 2/Week | Intrathecal Trastuzumab 20 mg IT will be administered in Cohort 2 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days. |
| OG002 | Cohort 3- Trastuzumab 40mg IT 2/Week | Intrathecal Trastuzumab 40 mg IT will be administered in Cohort 3 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days. |
| OG003 | Cohort 4 - Trastuzumab 60mg IT 2/Week | Intrathecal Trastuzumab 60 mg IT will be administered in Cohort 4 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days. |
| OG004 | Cohort 5 - 80mg IT 2/Week | Intrathecal Trastuzumab 80 mg IT will be administered in Cohort 5 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days. |
|
|
|
| Primary | Best Response to IT Trastuzumab: Radiological, Cytological and Clinical in Treatment With Intrathecal Trastuzumab for Patients With Leptomeningeal Metastases in HER2+ Breast Cancer. | Best response will be assessed using a combination CSF cytology assessment, radiographic assessment and clinical function assessments. Best response will be defined as the best response seen during treatment as compared to baseline that is confirmed on subsequent response assessment. | All patients were assessed for response. Patients unable to be assessed were determined to have progressive disease and counted. Cohort results for this outcome measure were analysed combined and at the MTD of 80mg IT (Cohort 5 + phase II). The objective was to determine preliminary response data for this treatment combination. | Posted | Count of Participants | Participants | Baseline then at 4 weeks, 8 weeks and then every 8 weeks +/- 3 days, until disease progression or toxicity,range of cycles completed 1-22 cycles where 1 cycle = 28 days. |
|
|
|
| Other Pre-specified | Define the CSF PK of IT Trastuzumab. | Patients may need a CSF flow study at the discretion of the treating principal investigator. If a spinal block is seen by CSF flow study or MRI, it will need local RT prior to treatment. Concurrent radiation is not allowed. | Not Posted | CSF analysis for cytology will be done every 2 weeks when CSF is obtained for PK and then every 4 weeks | Participants |
| Post-Hoc | Progression Free Survival (PRS) at 6 Months and at 12 Months in Treatment With Intrathecal Trastuzumab for Patients With Leptomeningeal Metastases in HER2+ Breast Cancer. | Progression Free Survival (PFS) will be measured from the time of treatment initiation until the first documentation of progression. To estimate the probability of PFS at 6 months and 12 months, Kaplan-Meier curves will be calculated and PFS at 6 months and 12 months will be determined from the progression-free survival curve. Progression will be defined as worsening clinical signs or development of new clinical symptoms that the Investigator feels can be attributed to Leptomeningeal disease. | Cohort results for this outcome measure were analyzed both combined and for patients treated at the MTD dose of 80mg IT as the objective was to determine preliminary data on PFS of patients with this drug combination. | Posted | Number | Probability of Survival | At 6 and 12 months from start of treatment |
|
|
|
| Post-Hoc | Overall Survival (OS) at 6 and 12 Months in Treatment With Intrathecal Trastuzumab for Patients With Leptomeningeal Metastases in HER2+ Breast Cancer. | Overall Survival (OS) will be measured from the time of treatment initiation until death from any cause. To estimate OS probability at 6 and 12 months, Kaplan-Meier curves will be calculated and OS at 612 months will be determined from the overall survival curve. | Cohort results for this outcome measure were analyzed both combined and for patients treated at the MTD dose of 80mg IT as the objective was to determine preliminary data on OS of patients with this drug combination. | Posted | Number | Probability of Survival | At 6 and 12 months from start of treatment |
|
|
|
| Post-Hoc | Median Progression Free Survival (PFS) in Treatment With Intrathecal Trastuzumab for Patients With Leptomeningeal Metastases in HER2+ Breast Cancer. | Progression Free Survival (PFS) will be measured from the time of treatment initiation until the first documentation of progression. To estimate PFS, Kaplan-Meier curves will be calculated and the median PFS will be determined from the progression-free survival curve. Progression will be defined as worsening clinical signs or development of new clinical symptoms that the Investigator feels can be attributed to Leptomeningeal disease. | Cohort results for this outcome measure were analyzed both combined and for patients treated at the MTD dose of 80mg IT as the objective was to determine preliminary data on PFS of patients with this drug combination | Posted | Median | 95% Confidence Interval | Months | From start of treatment, and during treatment until progressive disease for up to 30 months. |
|
|
|
| Post-Hoc | Median Overall Survival (OS) in Treatment With Intrathecal Trastuzumab for Patients With Leptomeningeal Metastases in HER2+ Breast Cancer. | Overall Survival (OS) will be measured from start of treatment until death from any cause. To estimate OS, Kaplan-Meier curves will be calculated and median OS will be determined from the progression-free survival curve. | Cohort results for this outcome measure were analyzed both combined and for patients treated at the MTD dose of 80mg IT as the objective was to determine preliminary data on OS of patients with this drug combination | Posted | Median | 95% Confidence Interval | percentage of patients | From start of treatment until death from any cause for up to 60 months. |
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| 3 |
| 3 |
| 1 |
| 3 |
| 3 |
| 3 |
| EG001 | Cohort 2 - Trastuzumab 20mg IT 2/Week | Intrathecal Trastuzumab 20 mg IT will be administered in Cohort 2 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days. | 3 | 3 | 2 | 3 | 3 | 3 |
| EG002 | Cohort 3- Trastuzumab 40mg IT 2/Week | Intrathecal Trastuzumab 40 mg IT will be administered in Cohort 3 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days. | 1 | 1 | 1 | 1 | 1 | 1 |
| EG003 | Cohort 4 - Trastuzumab 60mg IT 2/Week | Intrathecal Trastuzumab 60 mg IT will be administered in Cohort 4 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days. | 1 | 1 | 1 | 1 | 1 | 1 |
| EG004 | Cohort 5 - 80mg IT 2/Week | Intrathecal Trastuzumab 80 mg IT will be administered in Cohort 5 of dose escalation. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days. | 5 | 7 | 3 | 7 | 7 | 7 |
| EG005 | Phase II - Transtuzumab 80mg IT 2/Week | Intrathecal Trastuzumab 10 mg IT will be administered in phase II portion of the study. Trastuzumab: Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks until disease progression or unacceptable toxicity. 1 cycle = 28 days. | 17 | 19 | 13 | 19 | 19 | 19 |
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| Dysphasia | Nervous system disorders | CTCAE (4.03) | Systematic Assessment |
|
| Seizure | Nervous system disorders | CTCAE (4.03) | Systematic Assessment |
|
| Chemical meningitis | Infections and infestations | CTCAE (4.03) | Systematic Assessment |
|
| Worsening Mental Status | Nervous system disorders | CTCAE (4.03) | Systematic Assessment |
|
| Hyponatremia | Metabolism and nutrition disorders | CTCAE (4.03) | Systematic Assessment |
|
| Abdominal muscle wall hemorrhage | Gastrointestinal disorders | CTCAE (4.03) | Systematic Assessment | Patient experienced abdominal pain during this event. |
|
| Syncope | Nervous system disorders | CTCAE (4.03) | Systematic Assessment |
|
| Death due to aspiration pneumonia | Respiratory, thoracic and mediastinal disorders | CTCAE (4.03) | Systematic Assessment |
|
| Dehydration | Gastrointestinal disorders | CTCAE (4.03) | Systematic Assessment | Patients experienced generalized weakness and abdominal pain during the inpatient hospitalization. |
|
| Gastroenteritis | Gastrointestinal disorders | CTCAE (4.03) | Systematic Assessment |
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| Dehydration | Gastrointestinal disorders | CTCAE (4.03) | Systematic Assessment |
|
| Esophagitis | Respiratory, thoracic and mediastinal disorders | CTCAE (4.03) | Systematic Assessment |
|
| Vasivagal reaction | Nervous system disorders | CTCAE (4.03) | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | CTCAE (4.03) | Systematic Assessment | Patient experienced nausea during this inpatient hospitalization. |
|
| Colonic perforation | Gastrointestinal disorders | CTCAE (4.03) | Systematic Assessment | Patient also experienced confusion during this inpatient hospitalization. |
|
| Abdominal pain | Gastrointestinal disorders | CTCAE (4.03) | Systematic Assessment |
|
| Thromboembolic event (DVT) | Vascular disorders | CTCAE (4.03) | Systematic Assessment | Patient also experienced pulmonary embolism during this inpatient hospitalization. |
|
| Death due to progressive disease | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | CTCAE (4.03) | Systematic Assessment |
|
| Pain in back and extremities | Musculoskeletal and connective tissue disorders | CTCAE (4.03) | Systematic Assessment | Patient also experienced Nausea and headache during this inpatient hospitalization |
|
| Lung infection | Infections and infestations | CTCAE (4.03) | Systematic Assessment |
|
| Clinical deterioration | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | CTCAE (4.03) | Systematic Assessment |
|
| Wound infection | Infections and infestations | CTCAE (4.03) | Systematic Assessment |
|
| Worsening neurological symptoms | Nervous system disorders | CTCAE (4.03) | Systematic Assessment |
|
| Enterocolitis infectious | Infections and infestations | CTCAE (4.03) | Systematic Assessment |
|
| Muscle weakness | Musculoskeletal and connective tissue disorders | CTCAE (4.03) | Systematic Assessment | Patient also experienced gait disturbance during this hospitalization. |
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| Hydrocephalus | Nervous system disorders | CTCAE (4.03) | Systematic Assessment | Patient also experienced somnolence during this hospitalization. |
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| Arachnoiditis | Nervous system disorders | CTCAE (4.03) | Systematic Assessment |
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| Febrile neutropenia | Blood and lymphatic system disorders | CTCAE (4.03) | Systematic Assessment |
|
| Palpitations | Cardiac disorders | CTCAE (4.03) | Systematic Assessment |
|
| Hearing impaired | Ear and labyrinth disorders | CTCAE (4.03) | Systematic Assessment |
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| Tinnitus | Ear and labyrinth disorders | CTCAE (4.03) | Systematic Assessment |
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| Blurred vision | Eye disorders | CTCAE (4.03) | Systematic Assessment |
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| Abdominal pain | Gastrointestinal disorders | CTCAE (4.03) | Systematic Assessment |
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| Constipation | Gastrointestinal disorders | CTCAE (4.03) | Systematic Assessment |
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| Diarrhea | Gastrointestinal disorders | CTCAE (4.03) | Systematic Assessment |
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| Dry mouth | Gastrointestinal disorders | CTCAE (4.03) | Systematic Assessment |
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| Dysphagia | Gastrointestinal disorders | CTCAE (4.03) | Systematic Assessment |
|
| Fecal incontinence | Gastrointestinal disorders | CTCAE (4.03) | Systematic Assessment |
|
| Hemorrhoids | Gastrointestinal disorders | CTCAE (4.03) | Systematic Assessment |
|
| Mucositis oral | Gastrointestinal disorders | CTCAE (4.03) | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | CTCAE (4.03) | Systematic Assessment |
|
| Upper gastrointestinal hemorrhage | Gastrointestinal disorders | CTCAE (4.03) | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | CTCAE (4.03) | Systematic Assessment |
|
| Decreased appetite | Gastrointestinal disorders | CTCAE (4.03) | Systematic Assessment |
|
| Chills | Gastrointestinal disorders | CTCAE (4.03) | Systematic Assessment |
|
| Edema in limbs | General disorders | CTCAE (4.03) | Systematic Assessment |
|
| Edema in head | General disorders | CTCAE (4.03) | Systematic Assessment |
|
| Fatigue | General disorders | CTCAE (4.03) | Systematic Assessment |
|
| Fever | General disorders | CTCAE (4.03) | Systematic Assessment |
|
| Flu like symptoms | General disorders | CTCAE (4.03) | Systematic Assessment |
|
| Gait disturbance | General disorders | CTCAE (4.03) | Systematic Assessment |
|
| Non-cardiac Chest Pain | General disorders | CTCAE (4.03) | Systematic Assessment |
|
| Pain | General disorders | CTCAE (4.03) | Systematic Assessment |
|
| Lung infection | Infections and infestations | CTCAE (4.03) | Systematic Assessment |
|
| Paronychia | Infections and infestations | CTCAE (4.03) | Systematic Assessment |
|
| Skin infection | Infections and infestations | CTCAE (4.03) | Systematic Assessment |
|
| Urinary tract infection | Infections and infestations | CTCAE (4.03) | Systematic Assessment |
|
| Vaginal infection | Infections and infestations | CTCAE (4.03) | Systematic Assessment |
|
| Fall | Injury, poisoning and procedural complications | CTCAE (4.03) | Systematic Assessment |
|
| Dermatitis radiation | Injury, poisoning and procedural complications | CTCAE (4.03) | Systematic Assessment |
|
| Activated Partial Thromboplastin Time Prolonged | Investigations | CTCAE (4.03) | Systematic Assessment |
|
| Alanine Aminotransferase Increased | Investigations | CTCAE (4.03) | Systematic Assessment |
|
| Alkaline Phosphatase Increased | Investigations | CTCAE (4.03) | Systematic Assessment |
|
| Aspartate Aminotransferase Increased | Investigations | CTCAE (4.03) | Systematic Assessment |
|
| Blood Antidiuretic Hormone Abnormal | Investigations | CTCAE (4.03) | Systematic Assessment |
|
| Blood Bilirubin Increased | Investigations | CTCAE (4.03) | Systematic Assessment |
|
| Lymphocyte Count Decreased | Investigations | CTCAE (4.03) | Systematic Assessment |
|
| Neutrophil Count Decreased | Investigations | CTCAE (4.03) | Systematic Assessment |
|
| Platelet Count Decreased | Investigations | CTCAE (4.03) | Systematic Assessment |
|
| White Blood Cell Decreased | Investigations | CTCAE (4.03) | Systematic Assessment |
|
| Dehydration | Metabolism and nutrition disorders | CTCAE (4.03) | Systematic Assessment |
|
| Hyperglycemia | Metabolism and nutrition disorders | CTCAE (4.03) | Systematic Assessment |
|
| Hypernatremia | Metabolism and nutrition disorders | CTCAE (4.03) | Systematic Assessment |
|
| Hypoalbuminemia | Metabolism and nutrition disorders | CTCAE (4.03) | Systematic Assessment |
|
| Hypocalcemia | Metabolism and nutrition disorders | CTCAE (4.03) | Systematic Assessment |
|
| Hypoglycemia | Metabolism and nutrition disorders | CTCAE (4.03) | Systematic Assessment |
|
| Hypokalemia | Metabolism and nutrition disorders | CTCAE (4.03) | Systematic Assessment |
|
| Hypomagnesemia | Metabolism and nutrition disorders | CTCAE (4.03) | Systematic Assessment |
|
| Hyponatremia | Metabolism and nutrition disorders | CTCAE (4.03) | Systematic Assessment |
|
| Back Pain | Musculoskeletal and connective tissue disorders | CTCAE (4.03) | Systematic Assessment |
|
| Buttock Pain | Musculoskeletal and connective tissue disorders | CTCAE (4.03) | Systematic Assessment |
|
| Generalized Muscle Weakness | Musculoskeletal and connective tissue disorders | CTCAE (4.03) | Systematic Assessment |
|
| Muscle Weakness Lower Limb | Musculoskeletal and connective tissue disorders | CTCAE (4.03) | Systematic Assessment |
|
| Muscle Weakness Upper Limb | Musculoskeletal and connective tissue disorders | CTCAE (4.03) | Systematic Assessment |
|
| Neck Pain | Musculoskeletal and connective tissue disorders | CTCAE (4.03) | Systematic Assessment |
|
| Pain in Extremity | Musculoskeletal and connective tissue disorders | CTCAE (4.03) | Systematic Assessment |
|
| Abducens Nerve Disorder | Nervous system disorders | CTCAE (4.03) | Systematic Assessment |
|
| Dizziness | Nervous system disorders | CTCAE (4.03) | Systematic Assessment |
|
| Dysgeusia | Nervous system disorders | CTCAE (4.03) | Systematic Assessment |
|
| Headaches | Nervous system disorders | CTCAE (4.03) | Systematic Assessment |
|
| Lethargy | Nervous system disorders | CTCAE (4.03) | Systematic Assessment |
|
| Memory Impairment | Nervous system disorders | CTCAE (4.03) | Systematic Assessment |
|
| Meningismus | Nervous system disorders | CTCAE (4.03) | Systematic Assessment |
|
| Involuntary Movements | Nervous system disorders | CTCAE (4.03) | Systematic Assessment |
|
| Oculomotor Nerve Disorder | Nervous system disorders | CTCAE (4.03) | Systematic Assessment |
|
| Peripheral Sensory Neuropathy | Nervous system disorders | CTCAE (4.03) | Systematic Assessment |
|
| Seizure | Nervous system disorders | CTCAE (4.03) | Systematic Assessment |
|
| Syncope | Nervous system disorders | CTCAE (4.03) | Systematic Assessment |
|
| Paresthesia | Nervous system disorders | CTCAE (4.03) | Systematic Assessment |
|
| Aphasia | Nervous system disorders | CTCAE (4.03) | Systematic Assessment |
|
| Gait difficulty | Nervous system disorders | CTCAE (4.03) | Systematic Assessment |
|
| Anxiety | Psychiatric disorders | CTCAE (4.03) | Systematic Assessment |
|
| Confusion | Psychiatric disorders | CTCAE (4.03) | Systematic Assessment |
|
| Insomnia | Psychiatric disorders | CTCAE (4.03) | Systematic Assessment |
|
| Urinary incontinence | Renal and urinary disorders | CTCAE (4.03) | Systematic Assessment |
|
| Urinary Frequency | Renal and urinary disorders | CTCAE (4.03) | Systematic Assessment |
|
| Allergic Rhinitis | Respiratory, thoracic and mediastinal disorders | CTCAE (4.03) | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | CTCAE (4.03) | Systematic Assessment |
|
| Epistaxis | Respiratory, thoracic and mediastinal disorders | CTCAE (4.03) | Systematic Assessment |
|
| Hoarseness | Respiratory, thoracic and mediastinal disorders | CTCAE (4.03) | Systematic Assessment |
|
| Hypoxia | Respiratory, thoracic and mediastinal disorders | CTCAE (4.03) | Systematic Assessment |
|
| Pneumonitis | Respiratory, thoracic and mediastinal disorders | CTCAE (4.03) | Systematic Assessment |
|
| Respiratory Failure | Respiratory, thoracic and mediastinal disorders | CTCAE (4.03) | Systematic Assessment |
|
| Alopecia | Skin and subcutaneous tissue disorders | CTCAE (4.03) | Systematic Assessment |
|
| Dry Skin | Skin and subcutaneous tissue disorders | CTCAE (4.03) | Systematic Assessment |
|
| Pain of Skin | Skin and subcutaneous tissue disorders | CTCAE (4.03) | Systematic Assessment |
|
| Rash Acneiform | Skin and subcutaneous tissue disorders | CTCAE (4.03) | Systematic Assessment |
|
| Rash Maculo-papular | Skin and subcutaneous tissue disorders | CTCAE (4.03) | Systematic Assessment |
|
| Hand and Foot Syndrome | Skin and subcutaneous tissue disorders | CTCAE (4.03) | Systematic Assessment |
|
| Hematuria | Vascular disorders | CTCAE (4.03) | Systematic Assessment |
|
| Hypertension | Vascular disorders | CTCAE (4.03) | Systematic Assessment |
|
| Hypotension | Vascular disorders | CTCAE (4.03) | Systematic Assessment |
|
| Hot Flashes | Vascular disorders | CTCAE (4.03) | Systematic Assessment |
|
| Lymphedema | Vascular disorders | CTCAE (4.03) | Systematic Assessment |
|
| Thromboembolic Event | Vascular disorders | CTCAE (4.03) | Systematic Assessment |
|
Not provided
Not provided
Not provided
| D017437 |
| Skin and Connective Tissue Diseases |
| D007162 |
| Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
| Stable Disease |
|
| Progressive Disease |
|