Clinical trial NCT01325207: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Breast Cancer
Keywords: Breast Cancer
Lead sponsor: Northwestern University
Sponsor class: OTHER
First posted: 2011-03-29
Enrollment: 34
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Number of Dose Limiting Toxicities (DLT) of IT Trastuzumab in Sequential Cohorts of Escalating Doses for Patients With Leptomeningeal Metastases in HER2+ Breast Cancer.
timeFrame: From treatment initiation through the first 4 weeks of treatment.
measure: Best Response to IT Trastuzumab: Radiological, Cytological and Clinical in Treatment With Intrathecal Trastuzumab for Patients With Leptomeningeal Metastases in HER2+ Breast Cancer.
timeFrame: 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.
Secondary outcomes:
Other outcomes:
measure: Define the CSF PK of IT Trastuzumab.
timeFrame: CSF analysis for cytology will be done every 2 weeks when CSF is obtained for PK and then every 4 weeks
Locations:
city: San Francisco
country: United States
facility: University of California San Francisco (UCSF)
state: California
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: New York
country: United States
facility: Columbia University
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Austin
country: United States
facility: Texas Oncology-Austin
state: Texas
Study officials:
affiliation: Northwestern University
name: Jeffrey Raizer, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.