Intrathecal Trastuzumab for Leptomeningeal Metastases in HER2+ Breast Cancer
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The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. |
| ClinicalTrials.gov Identifier: NCT01325207 |
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Recruitment Status :
Completed
First Posted : March 29, 2011
Results First Posted : May 28, 2019
Last Update Posted : September 26, 2019
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Breast Cancer | Radiation: Trastuzumab | Phase 1 Phase 2 |
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 34 participants |
| Intervention Model: | Sequential Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Phase I/II Dose Escalation Trial to Assess Safety of Intrathecal Trastuzumab for the Treatment of Leptomeningeal Metastases in HER2 Positive Breast Cancer |
| Study Start Date : | August 1, 2011 |
| Actual Primary Completion Date : | June 20, 2016 |
| Actual Study Completion Date : | January 20, 2019 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: intravenous trastuzumab infusions
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).
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Radiation: Trastuzumab
Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks
Other Names:
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- Number of Dose Limiting Toxicities (DLT) of IT Trastuzumab in Sequential Cohorts of Escalating Doses for Patients With Leptomeningeal Metastases in HER2+ Breast Cancer. [ Time Frame: From treatment initiation through the first 4 weeks of treatment. ]
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
- Best Response to IT Trastuzumab: Radiological, Cytological and Clinical in Treatment With Intrathecal Trastuzumab for Patients With Leptomeningeal Metastases in HER2+ Breast Cancer. [ Time Frame: 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. ]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.
- Define the CSF PK of IT Trastuzumab. [ Time Frame: CSF analysis for cytology will be done every 2 weeks when CSF is obtained for PK and then every 4 weeks ]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.
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
ELIGIBILITY CRITERIA
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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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01325207
| United States, California | |
| University of California San Francisco (UCSF) | |
| San Francisco, California, United States, 94143-1710 | |
| United States, Illinois | |
| Northwestern University | |
| Chicago, Illinois, United States, 60611 | |
| United States, Massachusetts | |
| Tufts Medical Center | |
| Boston, Massachusetts, United States, 02111 | |
| Dana Farber Cancer Institute | |
| Boston, Massachusetts, United States, 02215 | |
| United States, New York | |
| Columbia University | |
| New York, New York, United States, 10032 | |
| Memorial Sloan-Kettering Cancer Center | |
| New York, New York, United States, 10065 | |
| United States, Rhode Island | |
| Rhode Island Hospital | |
| Providence, Rhode Island, United States, 02903 | |
| United States, Texas | |
| Texas Oncology-Austin | |
| Austin, Texas, United States, 78705 | |
| Principal Investigator: | Jeffrey Raizer, MD | Northwestern University |
| Responsible Party: | Northwestern University |
| ClinicalTrials.gov Identifier: | NCT01325207 |
| Other Study ID Numbers: |
NU 10C03 STU00040150 ( Other Identifier: Northwestern University IRB ) |
| First Posted: | March 29, 2011 Key Record Dates |
| Results First Posted: | May 28, 2019 |
| Last Update Posted: | September 26, 2019 |
| Last Verified: | September 2019 |
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Breast Cancer |
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Breast Neoplasms Neoplasms by Site Neoplasms Breast Diseases |
Skin Diseases Trastuzumab Antineoplastic Agents, Immunological Antineoplastic Agents |