Clinical and Pharmacological Study With 2B3-101 in Patients With Breast Cancer and Leptomeningeal Metastases
- Registration Number
- NCT01818713
- Lead Sponsor
- The Netherlands Cancer Institute
- 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 Description
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% in patients between 50 and 69 years. \[6\] 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.
In the ongoing Phase I/IIa study (M11TBB) the safety and preliminary efficacy of 2B3-101 is being determined in patients with brain metastases of solid tumours and patients with recurrent malignant glioma in 7 hospitals in The Netherlands, Belgium, France and USA.
This a feasibility 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 (see table 2).
To examine the enhanced delivery of 2B3-101 in the central nervous system (brain and CSF), measurements of doxorubicin in the brain interstitial space or CSF are indicated. Technically, doxorubicin measurements in the brain interstitial space are difficult, as invasive probes (microdialysis or open probe) should be positioned in the brain tissue. Measurement of free doxorubicine in the CSF is easier as CSF can be obtained by a lumbar puncture in patients with LM treated with 2B3-101. Doxorubicine CSF levels will be compared with doxorubicine plasma levels. Doxorubicine will be measured as total doxorubicine (free doxorubicine + liposomal doxorubicine) and free doxorubicin.
To measure the anti-tumor response of 2B3-101 on leptomeningeal metastases we plan to explore enumeration of circulating tumor cells (CTC) prior to and during 2B3-101 therapy, using a fluorescence-activated cell sorting (FACS) flow cytometry method that is currently validated in the ongoing study N12CLM (NKI/AvL). The CTC method can determine single cell change in epithelial cell adhesion molecule (EpCAM) positive tumors, like breast cancer.
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- All
- Target Recruitment
- 6
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description 2B3-101 2B3-101 A single dose of 2B3-101 (a glutathione (GSH) pegylated liposomal doxorubicin hydrochloride formulation) will be administrated intravenously once per cycle. To minimize the risk of infusion reactions, 5% of the total dose of 2B3-101 (in mg) will be administrated over the first 30 minutes. If tolerated, the infusion may then be completed over the next hour for a total infusion time of 90 minutes
- Primary Outcome Measures
Name Time Method - safety and preliminary response using the "LM response score" during the 2B3-101 treatment in patients with LM from breast cancer. 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.
- Secondary Outcome Measures
Name Time Method - CNS progression free survival in patients with LM from breast cancer treated with 2B3-101. 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. one year every 2 cycles analyse and compare the measured plasma and CSF levels of free doxorubicin with MRI and pathologic reports
- the change in number of CTCs in CSF and blood and its correlation with the LM response score. one year measuring circulatory tumor cells in CSF and plasma every 2 cycles and comparing the change with the LM response score
- systemic progression free survival in patients with LM from breast cancer treated with 2B3-101. one year CT and MRI every 2 cycles
overall survival in patients with LM from breast cancer treated with 2B3-101. one year follow up till death
the change in number of CTCs in CSF and blood and its correlation with doxorubicine CSF and plasma levels. one year To determine the change in number of CTCs in CSF and blood and correlate this with doxorubicine CSF and plasma levels.
Trial Locations
- Locations (1)
the Netherlands Cancer Institute - Antoni van Leeuwenhoek
🇳🇱Amsterdam, Netherlands