Clinical Trials /

Intrathecal Trastuzumab for Leptomeningeal Metastases in HER2+ Breast Cancer

NCT01325207

Description:

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.

Related Conditions:
  • Breast Carcinoma
  • Ependymoma
  • Glioma
  • Medulloblastoma
Recruiting Status:

Completed

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Intrathecal Trastuzumab for Leptomeningeal Metastases in HER2+ Breast Cancer
  • 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

Clinical Trial IDs

  • ORG STUDY ID: NU 10C03
  • SECONDARY ID: STU00040150
  • NCT ID: NCT01325207

Conditions

  • Breast Cancer

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
intravenous trastuzumab infusionsExperimentalA 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).

    Eligibility Criteria

            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
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure: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
    Safety Issue:
    Description: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.

    Secondary Outcome Measures

    Measure: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
    Safety Issue:
    Description: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.
    Measure: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
    Safety Issue:
    Description: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.

    Details

    Phase:Phase 1/Phase 2
    Primary Purpose:Interventional
    Overall Status:Active, not recruiting
    Lead Sponsor:Northwestern University

    Trial Keywords

    • Breast Cancer

    Last Updated

    December 19, 2017