Intrathecal Trastuzumab for Leptomeningeal Metastases in HER2+ Breast Cancer

Phase 1

Completed

• Conditions: Breast Cancer
• Interventions: Radiation: Trastuzumab

• Registration Number: NCT01325207
• Lead Sponsor: Northwestern University

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.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2011-03-07
• Study First Submitted QC: 2011-03-28
• Study First Posted: 2011-03-29
• Study Start: 2011-08-01
• Primary Completion: 2016-06-20
• Study Completion: 2019-01-20
• Results First Submitted: 2019-04-05
• Results First Submitted QC: 2019-05-03
• Results First Posted: 2019-05-28
• Status Verified: 2019-09
• Last Update Submitted: 2019-09-03
• Last Update Posted: 2019-09-26

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 34

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.

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Exclusion Criteria

• Any deviations from the inclusion criteria

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
intravenous trastuzumab infusions	Trastuzumab	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).

Primary Outcome Measures

Name	Time	Method
Number of Dose Limiting Toxicities (DLT) of IT Trastuzumab in Sequential Cohorts of Escalating Doses for Patients With Leptomeningeal Metastases in HER2+ Breast Cancer.	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.	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.

Trial Locations

Locations (8)

Dana Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

Tufts Medical Center; 🇺🇸 Boston, Massachusetts, United States

University of California San Francisco (UCSF); 🇺🇸 San Francisco, California, United States

Northwestern University; 🇺🇸 Chicago, Illinois, United States

Columbia University; 🇺🇸 New York, New York, United States

Memorial Sloan-Kettering Cancer Center; 🇺🇸 New York, New York, United States

Texas Oncology-Austin; 🇺🇸 Austin, Texas, United States

Rhode Island Hospital; 🇺🇸 Providence, Rhode Island, United States