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Phase I/II Dose Escalation Trial to Assess Safety of Intrathecal Trastuzumab for the Treatment of Leptomeningeal Metastases in HER2 Positive Breast Cancer


Phase 1/Phase 2
18 Years
N/A
Open (Enrolling)
Both
Breast Cancer

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Trial Information

Phase I/II Dose Escalation Trial to Assess Safety of Intrathecal Trastuzumab for the Treatment of Leptomeningeal Metastases in HER2 Positive Breast Cancer


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.


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

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Determine the safety and maximum tolerated dose of IT trastuzumab.

Outcome 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.

Outcome Time Frame:

treated twice a week for 4 weeks, then once a week for 4 weeks, and then every 2 weeks

Safety Issue:

No

Principal Investigator

Jeffrey Raizer, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Northwestern University

Authority:

United States: Institutional Review Board

Study ID:

NU 10C03

NCT ID:

NCT01325207

Start Date:

April 2011

Completion Date:

March 2015

Related Keywords:

  • Breast Cancer
  • Breast Cancer
  • Breast Neoplasms
  • Neoplasm Metastasis
  • Meningeal Carcinomatosis

Name

Location

Memorial Sloan-Kettering Cancer CenterNew York, New York  10021
Northwestern UniversityChicago, Illinois  60611