Intrathecal Trastuzumab for Leptomeningeal Metastases in HER2+ Breast Cancer

• ClinicalTrials.gov Identifier: NCT01325207
• Recruitment Status: Completed
• First Posted: March 29, 2011
• Results First Posted: May 28, 2019
• Last Update Posted: September 26, 2019
• Sponsor: Northwestern University
• Information provided by (Responsible Party): Northwestern University

Tracking Information

• First Submitted Date: March 7, 2011
• First Posted Date: March 29, 2011
• Results First Submitted Date: April 5, 2019
• Results First Posted Date: May 28, 2019
• Last Update Posted Date: September 26, 2019
• Study Start Date: August 1, 2011
• Actual Primary Completion Date: June 20, 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 3, 2019)

• 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.

Original Primary Outcome Measures (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.

• Current Secondary Outcome Measures: Not Provided

Original Secondary Outcome Measures (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.

Current Other Pre-specified Outcome Measures (submitted: May 3, 2019)

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 Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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

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: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Breast Cancer

Intervention

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 *: 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 2, 2016): 34
• Original Estimated Enrollment (submitted: March 28, 2011): 24
• Actual Study Completion Date: January 20, 2019
• Actual Primary Completion Date: June 20, 2016 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01325207
• Other Study ID Numbers: 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: Northwestern University
• Collaborators: Not Provided

Investigators

• Principal Investigator: Jeffrey Raizer, MD; Northwestern University

• PRS Account: Northwestern University
• Verification Date: September 2019