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

Phase 2
18 Years
Not Enrolling
Meningeal Carcinomatosis

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Trial Information

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
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 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.

Inclusion Criteria

Inclusion criteria:

1. Age ≥ 18 years.

2. Radiological or cytological evidence of clinically LM of pathologically confirmed
breast cancer.

3. Concomitant brain metastases are allowed

4. ECOG Performance Status ≤ 2.

5. Estimated life expectancy of at least 8 weeks.

6. Stable/decreasing dosage of steroids (e.g.dexamethasone) for 7 days prior to baseline

7. Use of non-enzyme inducing anti-epileptic drugs is allowed.

8. Toxicities incurred as a result of previous anticancer therapy (radiation therapy,
chemotherapy, or surgery) must be resolved to ≤ grade 2 (as defined by CTCAE version

9. Written informed consent according to local guidelines.

10. Local radiation of CNS symptomatic sites more than four weeks prior to start of the
study is allowed.

Exclusion criteria:

1. Less than 4 weeks from the last treatment of chemotherapy, biological therapy,
immunotherapy, endocrine therapy and less than 6 weeks for nitrosoureas and mitomycin

2. Less than 4 weeks from the last radiotherapy of the brain or spinal cord/cauda

3. Patients that have received a maximum cumulative dose of free (i.e., non-liposomal)
or liposomal doxorubicin > 360mg/m2 or free epirubicin > 600mg/m2

4. Current or recent (less than 4 weeks before first 2B3-101 treatment) treatment with
another investigational drug.

5. Any other current anticancer therapy

6. Inadequate bone marrow function, defined as: Absolute Neutrophil Count (ANC): < 1.5 x
109/L, or platelet count < 100 x 109/L or haemoglobin < 6 mmol/L.

7. Inadequate liver function

8. Inadequate renal function

9. Pregnancy or lactation

10. For female subjects of childbearing potential (defined as < 2 years after last
menstruation and not surgically sterile) and male subjects who are not surgically
sterile and with female partners of childbearing potential: absence of effective,
non-hormonal means of contraception (intrauterine contraceptive device, barrier
method of contraception in conjunction with spermicidal gel).

11. Major surgical procedure (including open biopsy, excluding central line IV and
Port-a-cath) within 4 weeks prior to the first study treatment, or anticipation of
the need for major surgery during the course of the study treatment.

12. Grade 3 or 4 motor, sensory, or cranial neuropathy symptoms (as defined by CTCAE
version 4.0) caused by previous chemotherapy.

13. Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic >100mm Hg).

14. Clinically significant (i.e. active) cardiovascular disease defined as:

- Stroke within 6 months prior to treatment with 2B3-101 (day 1);

- Transient Ischaemic Attack (TIA) within 6 months prior to day 1;

- Myocardial infarction (MI) within ≤ 6 months prior to day 1;

- Unstable angina pectoris (AP);

- New York Heart Association (NYHA) Grade II or greater Congestive Heart Failure

- Cardiac arrhythmia, except stable atrium fibrillations;

15. LVEF by MUGA or ECHO < 50%.

16. Known hypersensitivity to any of the study drug components or its excipients
(doxorubicin, PEG or GSH).

17. Evidence of any other medical conditions that may interfere with the planned
treatment, affect patient compliance or place the patient at high risk from
treatment-related complications.

18. Contra-indications for lumbar punctures:

- blood clotting disorders (INR>1.5, platelets <20x109 /l, aPTT > 1.5 ULN). Lumbar
puncture after platelets transfusion resulting into platelets > 20x109 /l after
transfusion is allowed.

- therapeutic anticoagulant treatment that cannot be interrupted for 24 hours. Low
dose prophylactic treatment with low molecular weight heparins is allowed.

- cerebral space-occupying lesions with a risk of cerebral herniation.

- spinal space-occupying lesions with a risk of myelocompression or conus/cauda

19. Active systemic or CNS infection.

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

- safety and preliminary response using the "LM response score" during the 2B3-101 treatment in patients with LM from breast cancer.

Outcome Description:

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.

Outcome Time Frame:

one year

Safety Issue:


Principal Investigator

D. Brandsma, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:



Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Study ID:




Start Date:

March 2013

Completion Date:

April 2014

Related Keywords:

  • Meningeal Carcinomatosis
  • 2B3-101, liposomal doxorubicin, leptomeningeal metastases
  • Breast Neoplasms
  • Neoplasm Metastasis
  • Carcinoma
  • Meningeal Carcinomatosis