Intrathecal Trastuzumab for Leptomeningeal Metastases in HER2+ Breast Cancer

NCT01325207 | Completed Phase 1 Results DMC

• 2 other identifiers: NU 10C03STU00040150
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 8

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.

Conditions

Breast Cancer

Keywords

Breast Cancer

Outcome Measures

Primary Outcomes (2)

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

  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

  From treatment initiation through the first 4 weeks of treatment.

• Best Response to IT Trastuzumab: Radiological, Cytological and Clinical in Treatment With Intrathecal Trastuzumab for Patients With Leptomeningeal Metastases in HER2+ Breast Cancer.

  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.

  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.

Other Outcomes (1)

• Define the CSF PK of IT Trastuzumab.

  CSF analysis for cytology will be done every 2 weeks when CSF is obtained for PK and then every 4 weeks

Study Arms (1)

intravenous trastuzumab infusions

EXPERIMENTAL

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).

Radiation: Trastuzumab

Interventions

Trastuzumab RADIATION

Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks

Also known as: (also known as Herceptin, which, is a medicine that is used to slow or stop the growth of a cancerous tumor)

intravenous trastuzumab infusions

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

Sponsors & Collaborators

• Northwestern University: lead

Study Sites (8)

University of California San Francisco (UCSF)

San Francisco, California, 94143-1710, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

Tufts Medical Center

Boston, Massachusetts, 02111, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Columbia University

New York, New York, 10032, United States

Location

Memorial Sloan-Kettering Cancer Center

New York, New York, 10065, United States

Location

Rhode Island Hospital

Providence, Rhode Island, 02903, United States

Location

Texas Oncology-Austin

Austin, Texas, 78705, United States

Location

Related Publications (1)

• 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.

  PMID: 32506369 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Trastuzumab

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Jeffrey Raizer, MD
• Organization: Northwestern University

Jeffrey.Raizer@nm.org

Study Officials

• Jeffrey Raizer, MD

  Northwestern University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 7, 2011
• First Posted: March 29, 2011
• Study Start: August 1, 2011
• Primary Completion: June 20, 2016
• Study Completion: January 20, 2019
• Last Updated: September 26, 2019
• Results First Posted: May 28, 2019

Record last verified: 2019-09

Locations

US (8)