Clinical and pharmacological feasibility study with 2B3-101 in patients with breast cancer and leptomeningeal metastases

Recruitment & Eligibility

Status: Pending

Sex: Not specified

Target Recruitment: 6

Inclusion Criteria

1. Age >= 18 years.
2. Radiological or cytological evidence of clinically symptomatic leptomeningeal metastases 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 or decreasing dosage of steroids (e.g.dexamethason) for 7 days prior to baseline MRI 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 4.0).
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.
11. Previous trastuzumab treatment will be allowed to continue without
interruption in patients with histologically-confirmed HER2-positive (IHC 3+ or fluorescence in situ hybridization [FISH] amplified; by
clinical assay on either primary or metastatic tumor) adenocarcinoma of the breast

Exclusion Criteria

Candidates will be excluded from study entry if any of the following exclusion criteria exist:
Prior Treatment:
1. Less than 1 week since the last treatment of lapatinib, dabrafenib, everolimus, capecitabine, anastrazole, letrozole and exemestane; less than 2 weeks since the last treatment of vemurafenib; less than 4 weeks from the last treatment of trametinib, chemotherapy, biological therapy, immunotherapy and systemic radiotherapy (except palliative radiation delivered to <20% of bone marrow); less than 6 weeks for nitrosoureas and mitomycin C Previous trastuzumab treatment will be allowed to continue without interruption in patients with HER2+ breast
2. Radiotherapy of the brain or spinal cord/cauda equine or symptomatic bone metastases is allowed before or during 2B3-101 treatment both as single agent and in combination with trastuzumab but radiated localizations will not be used for response evaluation.
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
Haematology, coagulation and biochemistry:
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, defined as:
• Serum (total) bilirubin > 1.5 x the Upper Limit of Normal (ULN) for the institution in absence of liver metastases (> 2 x ULN in patients with liver metastases);
• Aspartate Amino Transferase (ASAT) or Alanine Amino Transferase (ALAT) > 3 x ULN if no liver metastases (> 5x ULN in patients with liver metastases);
• Alkaline phosphatase levels > 2.5 x ULN if no liver metastases (> 5 x ULN in patients with liver metastases, or > 10 x ULN in patients with bone metastases).
8. Inadequate renal function, defined as:
• Serum creatinine clearance < 50 ml/min ;Other:
9. Pregnancy or lactation. A serum pregnancy test needs to be performed within 7 days prior to study treatment start in case of childbearing potential, or within 14 days followed by a confirmatory urine pregnancy test within 7 days prior to study treatment start.
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

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>LM response score</p><br>

Secondary Outcome Measures

Name	Time	Method
<p>- safety profile in patients with LM from breast cancer treated with 2B3-101<br /><br>as single agent or in combination with trastuzumab<br /><br>- CNS progression free survival<br /><br>- correlation of the clinical and radiological findings (MRI) and CSF cytology<br /><br>with free doxorubicin levels in CSF and in plasma<br /><br>- systemic progression free survival<br /><br>- overall survival<br /><br>- change in number of CTCs in CSF and blood and its correlion with the LM<br /><br>response score<br /><br>- change in number of CTCs in CSF and blood and its correlation with free<br /><br>doxorubicine CSF and plasma levels</p><br>

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