Clinical and Pharmacological Study With 2B3-101 in Patients With Breast Cancer and Leptomeningeal Metastases
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
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.  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 and Belgium.
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.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
- safety and preliminary response using the "LM response score" during the 2B3-101 treatment in patients with LM from breast cancer.
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.
D. Brandsma, MD, PhD
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)