Clinical Trial: Clinical and Pharmacological Study With 2B3-101 in Patients With Breast Cancer and Leptomeningeal Metastases

Study Status: Recruiting
Recruit Status: Unknown status
Study Type: Interventional

Official Title: Clinical and Pharmacological Study With 2B3-101 in Patients With Breast Cancer and Leptomeningeal Metastases

Brief Summary:

Leptomeningeal metastases (LM) develop when tumor cells reach the cerebrospinal fluid (CSF) and infiltrate the leptomeninges. The median survival of patient with breast cancer and LM is 4-6 months with up to 25% long-term survivors. Many potentially highly efficacious intravenous chemotherapies are currently not effective to treat LM because they do not adequately cross the blood-CSF barrier.

Doxorubicin, the anthracycline chemotherapeutic agent, has a well-established antineoplastic activity in breast cancer. To optimally enhance the delivery of liposomal doxorubicin to the brain, to-BBB technologies B.V. has designed a glutathione (GSH) pegylated liposomal doxorubicin hydrochloride formulation (2B3-101). Coating of liposomes with PEG ensures the prolonged circulation time in plasma, whilst conjugation of GSH to the tips of the PEG molecules targets the liposomes towards the active GSH transporters on the BBB to enhance the delivery of doxorubicin to the brain.

This is a a clinical and pharmacological study that aims to determine preliminary efficacy of treatment with 2B3-101 in patients with leptomeningeal metastases of breast cancer using the LM response score.


Detailed Summary:

Leptomeningeal metastases (LM) develop when tumor cells reach the cerebrospinal fluid (CSF) and infiltrate the leptomeninges. Clinically symptomatic LM affects approximately 5 percent of patients with metastatic cancer. Among patients with LM caused by solid tumors, the most common tumor types are breast cancer (12-35%), lung cancer (10-26%), melanoma (5-25%) and gastrointestinal malignancies (4-14%). One to seven percent of LM patients have an unknown primary tumor.

The median survival of untreated patients with LM derived from solid tumors is only 6-8 weeks. Chemotherapy and radiotherapy of symptomatic central nervous system (CNS) sites extends the median survival up to 2-4 months. The median survival of patient with breast cancer and LM is even longer (4-6 months) with up to 25% long-term survivors. Many potentially highly efficacious intravenous chemotherapies are currently not effective to treat LM because they do not adequately cross the blood-CSF barrier. The effectiveness of intrathecal (IT) chemotherapy is thought to be limited due to rapid cerebrospinal fluid (CSF) clearance of the drug and/or insufficient penetration into larger (>1mm) tumor deposits in the subarachnoid space. Besides, only a few cytostatic drugs can be administered intrathecally because of neurotoxicity.

Doxorubicin, the anthracycline chemotherapeutic agent, has a well-established antineoplastic activity in breast cancer. It has triple action mechanisms, namely binding to the DNA strands by intercalation, blocking the enzyme topoisomerase II, necessary for DNA replication and formation of free radicals. The treatment of breast cancer patients with anthracycline-containing adjuvant chemotherapy reduces the relative risk (RR) of mortality in breast cancer patients with ± 38% per year in patients younger than 50 years and with ± 20% i
Sponsor: The Netherlands Cancer Institute

Current Primary Outcome: - safety and preliminary response using the "LM response score" during the 2B3-101 treatment in patients with LM from breast cancer. [ Time Frame: one year ]

All adverse events will be collected during the safety visits and summarized during the analysis using descriptive statistics. The data reported every 2 cycles by de radiologist (MRI reports), pathologist (CSF cytology) and neurologist (clinical response) will be compared using specially designed "LM response score" for this study.


Original Primary Outcome: - To determine the safety and preliminary response using the "LM response score" during the 2B3-101 treatment in patients with LM from breast cancer. [ Time Frame: one year ]

All adverse events will be collected during the safety visits and summarized during the analysis using descriptive statistics. The data reported every 2 cycles by de radiologist (MRI reports), pathologist (CSF cytology) and neurologist (clinical response) will be compared using specially designed "LM response score" for this study.


Current Secondary Outcome:

  • - CNS progression free survival in patients with LM from breast cancer treated with 2B3-101. [ Time Frame: one year ]
    MRI every 2 cycles
  • - collecting clinical and radiological findings (MRI) and CSF cytology and comparing them with doxorubicin levels in CSF and in plasma during the treatment of patients with LM from breast cancer with 2B3-101. [ Time Frame: one year ]
    every 2 cycles analyse and compare the measured plasma and CSF levels of free doxorubicin with MRI and pathologic reports
  • - systemic progression free survival in patients with LM from breast cancer treated with 2B3-101. [ Time Frame: one year ]
    CT and MRI every 2 cycles
  • overall survival in patients with LM from breast cancer treated with 2B3-101. [ Time Frame: one year ]
    follow up till death
  • - the change in number of CTCs in CSF and blood and its correlation with the LM response score. [ Time Frame: one year ]
    measuring circulatory tumor cells in CSF and plasma every 2 cycles and comparing the change with the LM response score
  • the change in number of CTCs in CSF and blood and its correlation with doxorubicine CSF and plasma levels. [ Time Frame: one year ]
    To determine the change in number of CTCs in CSF and blood and correlate this with doxorubicine CSF and plasma levels.


Original Secondary Outcome:

  • - To determine CNS progression free survival in patients with LM from breast cancer treated with 2B3-101. [ Time Frame: one year ]
    MRI every 2 cycles
  • - To correlate the clinical and radiological findings (MRI) and CSF cytology with doxorubicin levels in CSF and in plasma during the treatment of patients with LM from breast cancer with 2B3-101. [ Time Frame: one year ]
    analyse and compare the measured plasma and CSF levels of free doxorubicin with MRI and pathologic reports
  • - To determine systemic progression free survival in patients with LM from breast cancer treated with 2B3-101. [ Time Frame: one year ]
    CT and MRI every 2 cycles
  • To determine overall survival in patients with LM from breast cancer treated with 2B3-101. [ Time Frame: one year ]
    follow up till death
  • - To determine the change in number of CTCs in CSF and blood and correlate this with the LM response score. [ Time Frame: one year ]
    measuring circulatory tumor cells in CSF and plasma every 2 cycles and comparing the change with the LM response score
  • To determine the change in number of CTCs in CSF and blood and correlate this with doxorubicine CSF and plasma levels. [ Time Frame: one year ]
    To determine the change in number of CTCs in CSF and blood and correlate this with doxorubicine CSF and plasma levels.


Information By: The Netherlands Cancer Institute

Dates:
Date Received: March 18, 2013
Date Started: October 2013
Date Completion: October 2014
Last Updated: October 28, 2013
Last Verified: October 2013