Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Symptoms and General Pathology

Nervous System Diseases

Breast Neoplasms

Neoplasm Metastasis

Meningeal Carcinomatosis

Carcinoma

Neoplastic Processes

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Meningeal Neoplasms

Central Nervous System Neoplasms

Nervous System Neoplasms

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Doxorubicin

Liposomal doxorubicin

Anti-Bacterial Agents

Antibiotics, Antitubercular

Enzyme Inhibitors

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

50 mg/m2 2B3-101 intravenous 3-weekly administration

2B3-101

D. Brandsma, MD, PhD

B. Milojkovic Kerklaan, MD

D Brandsma, MD, PhD

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.

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.

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

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.

every 2 cycles analyse and compare the measured plasma and CSF levels of free doxorubicin with MRI and pathologic reports

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.

The Netherlands Cancer Institute

Respiratory Tract (Lung and Bronchial) Diseases

Lung Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

li-kun chen, Doctor

li-kun chen, doctor

li-kun Chen, Doctor

The primary purpose of this study is to compare the positive rate between the cell-free DNA and cytological examination of cerebrospinal fluid in Advanced lung cancer with leptomeningeal metastases.

A Prospective, Observational Trial on the Diagnostic and Prognostic of LM

A Prospective, Observational Trial on the Diagnostic and Prognostic Value of Cell-free DNA in Advanced Lung Cancer With Leptomeningeal Metastases

Sun Yat-sen University

associate professor

Immune System Diseases

Hypersensitivity

Neoplastic Cells, Circulating

Using extra CSF material received by clinically indicated lumbar punctures to determine the sensitivity and specificity of CTCs in CSF (5ml CSF). Standard material of 5 ml CSF for cytology and 2 ml CSF for cell count and chemistry is being regularly used and processed.

lumbar puncture

The purpose of this study is to determine whether the quantitative detection of circulating tumor cells (CTCs) in patients with Epcam expressing tumors can be used compared to standard qualitative method - cytology both in the cerebrospinal fluid of patients, clinically suspected for leptomeningeal metastases.

Leptomeningeal metastases (LM), is a diffuse dissemination of tumor cells into the cerebrospinal fluid (CSF) and leptomeninges.\[1\] Up to 8% of all patients with cancer develop LM. Gadolinium enhanced MRI of the symptomatic location of the nervous system is the radiological method of choice when LM is clinically suspected. In patients with a metastasized tumor, based on clinical signs of LM and contrast enhancement of either the leptomeninges, pia mater/cortex or cranial or spinal nerves on MRI, the diagnosis LM can be made. The sensitivity of MRI with gadolineum for LM is 75% and the specificity 77%. If MRI does not show equivocal abnormalities, CSF cytology needs to be performed. In 55% of patients with LM from solid tumors, malignant cells are found during the first CSF examination. The sensitivity raises to 80-90% after the second CSF sampling, as determined in the pre-MRI era. The volume of sampled CSF determines partly the sensitivity of CSF cytology. If possible, 10 ml CSF needs to be taken and the material must be processed as quickly as possible.

Recently, Patel et al (2011) described the detection of breast cancer cells in the CSF using the Cell Search System (Veridex). \[6\] Using this method, the CSF is enriched immuno-magnetically for the epithelial cell adhesion molecule (EpCAM). Next nuclear staining with 4 ',6-diamidino-2-phenylindole (DAPI) and immunofluorescent detection with cytokeratin and CD45 is performed in 5 patients with leptomeningeal metastases from breast cancer and approximately 104 circulating tumor cells (CTCs)in 7,5 ml CSF were found, using this method. There seemed to be an association between the number of CTCs and response to intrathecal administered chemotherapy in this small group of patients.

In the future, the determination of CTCs in the CSF could be a new quantitative method for the anti-tumor response assessment of systemic or intrathecal therapy (as opposed to CSF cytology, which is subjective and not a quantitative method). If the method shows greater sensitivity than CSF cytology and can reliably measure single tumor cells, the sensitivity of CSF examination in patients with a clinical suspicion of LM will increase. Possibly, this method can also be used to detect micrometastases in the CSF in patients without neurological symptoms, but with a high risk of CNS metastases.

Circulating Tumor Cells and Cytology in Cerebrospinal Fluid of Patients Clinically Suspected for Leptomeningeal Metastases

Determining the Sensitivity and Specificity of Circulating Tumor Cells and Cytology in Cerebrospinal Fluid of Patients Clinically Suspected for Leptomeningeal Metastases

Antirheumatic Agents

Dermatologic Agents

Reproductive Control Agents

Micronutrients

Hematinics

Vitamins

Methotrexate

Antimetabolites

Folic Acid

Vitamin B Complex

Folic Acid Antagonists

Immunosuppressive Agents

Immunologic Factors

Folinic Acid

Folate

Vitamin B9

The quantity of methotrexate is different in the two groups.

methotrexate

Hui Bu

The main purpose of this study is to compare the effect of 10 mg and 15 mg methotrexate in the treatment of meningeal carcinomatosis.

Different Dose of Methotrexate for the Treatment of Meningeal Carcinomatosis

In accordance with the standard of CTCAE, an assessment will be assessed every month

In accordance with the standard of KPS(Karnofsky Performance Status,KPS) score, an assessment will be assessed every month

Study Principal Investigator

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Clinical and Pharmacological Study With 2B3-101 in Patients With Breast Cancer and Leptomeningeal Metastases	NCT01818713	Meningeal Carci...	2B3-101	18 Years -	The Netherlands Cancer Institute
A Prospective, Observational Trial on the Diagnostic and Prognostic of LM	NCT02607605	Lung Neoplasms Meningeal Carci...		18 Years - 75 Years	Sun Yat-sen University
A Prospective, Observational Trial on the Diagnostic and Prognostic of LM	NCT02607605	Lung Neoplasms Meningeal Carci...		18 Years - 75 Years	Sun Yat-sen University
Circulating Tumor Cells and Cytology in Cerebrospinal Fluid of Patients Clinically Suspected for Leptomeningeal Metastases	NCT01713699	Meningeal Carci...	lumbar puncture	18 Years -	The Netherlands Cancer Institute
Different Dose of Methotrexate for the Treatment of Meningeal Carcinomatosis	NCT02590510	Meningeal Carci...	methotrexate	14 Years -	Hebei Medical University
Different Dose of Methotrexate for the Treatment of Meningeal Carcinomatosis	NCT02590510	Meningeal Carci...	methotrexate	14 Years -	Hebei Medical University
Circulating Tumor Cells and Cytology in Cerebrospinal Fluid of Patients Clinically Suspected for Leptomeningeal Metastases	NCT01713699	Meningeal Carci...	lumbar puncture	18 Years -	The Netherlands Cancer Institute

Spots Global Cancer Trial Database for meningeal carcinomatosis