Intrathecal Trastuzumab for Leptomeningeal Metastases in HER2+ Breast Cancer

Tracking Information
First Submitted Date ICMJE	March 7, 2011
First Posted Date ICMJE	March 29, 2011
Last Update Posted Date	June 14, 2018
Study Start Date ICMJE	April 2011
Estimated Primary Completion Date	March 2019 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: March 28, 2011)	Determine the safety and maximum tolerated dose of IT trastuzumab. [ Time Frame: treated twice a week for 4 weeks, then once a week for 4 weeks, and then every 2 weeks ]; The initial phase of this study will be a dose escalation trial of 3-6 patients per each dose level. Dose escalation will occur until the MTD or the maximal defined dose (MDD) (40 mg) is reached. The starting dose will be 10 mg for cohort 1, 20 mg for cohort 2, 30 mg for cohort 3 and 40 mg for cohort 4. Patients will be treated twice a week for 4 weeks, then once a week for 4 weeks, and then every 2 weeks. The starting dose is based on the safety of this dose and higher doses as reported in the literature. The MTD or MDD will be used for phase II.
Original Primary Outcome Measures ICMJE	Same as current
Change History	Complete list of historical versions of study NCT01325207 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: March 28, 2011)	Determine response to IT trastuzumab: radiological, cytological and clinical. [ Time Frame: A baseline enhanced MRI of the brain and spine within 14 days of registration. The first follow up MRI of the brain and spine will be done after 4 weeks then every 6-8 weeks +/- 3 days for each ]A baseline MRI of the brain and spine within 14 days of registration. Follow up MRI of the brain and spine,at 4 weeks then every 6-8 weeks. CT chest/abdomen/pelvis is optional but will be ordered if needed to assess systemic disease and any response.; 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.
Original Secondary Outcome Measures ICMJE	Same as current
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Intrathecal Trastuzumab for Leptomeningeal Metastases in HER2+ Breast Cancer
Official Title ICMJE	Phase I/II Dose Escalation Trial to Assess Safety of Intrathecal Trastuzumab for the Treatment of Leptomeningeal Metastases in HER2 Positive Breast Cancer
Brief Summary	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.
Detailed Description	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.
Study Type ICMJE	Interventional
Study Phase	Phase 1; Phase 2
Study Design ICMJE	Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	Breast Cancer
Intervention ICMJE	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: (also known as Herceptin, which; is a medicine that is used to slow or stop the growth of a cancerous tumor)
Study Arms	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).; Intervention: Radiation: Trastuzumab
Publications *	Not Provided
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Active, not recruiting
Actual Enrollment ICMJE; (submitted: June 2, 2016)	34
Original Estimated Enrollment ICMJE; (submitted: March 28, 2011)	24
Estimated Study Completion Date	March 2020
Estimated Primary Completion Date	March 2019 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	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
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years and older (Adult, Older Adult)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT01325207
Other Study ID Numbers ICMJE	NU 10C03; STU00040150 ( Other Identifier: Northwestern University IRB )
Has Data Monitoring Committee	Yes
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	Northwestern University
Study Sponsor ICMJE	Northwestern University
Collaborators ICMJE	Not Provided
Investigators ICMJE	Principal Investigator: Jeffrey Raizer, MD Northwestern University
PRS Account	Northwestern University
Verification Date	June 2018
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP