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

Conditions: Patients with leptomeningeal metastases of breast cancer will be enrolled.
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2012-005096-13-NL

Lead Sponsor: the Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital (NKI-AvL)

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: Not specified

Inclusion Criteria

1. Age = 18 years.
2. Radiological or cytological evidence of clinically symptomatic leptomeningeal metastases of breast cancer.
3. Stable or decreasing dosage of steroids (e.g.dexamethason) for 7 days prior to baseline MRI or non-enzyme inducing anti-epileptic drugs is allowed.
4. Concomitant brain metastases are allowed
5. Patients with pathologically confirmed diagnosis of advanced, recurrent breast cancer and unequivocal evidence of leptomeningeal metastases
6. ECOG Performance Status = 2.
7. Estimated life expectancy of at least 8 weeks.
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. Performed cognitive test for neurotoxicity
10. Written informed consent according to local guidelines.
11. Local radiation of CNS symptomatic sites more than four weeks prior to start of the study is allowed.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 6
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion Criteria

Candidates will be excluded from study entry if any of the following exclusion criteria exist:
Prior Treatment:
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 C.
2. Less than 4 weeks from the last radiotherapy of the brain or spinal cord/cauda equina. Radiotherapy of the symptomatic bone metastases is allowed during 2B3-101 treatment but if they are located in the vertebral column, these radiated localisations cannot 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 is not allowed, as there are no interaction data of combination of 2B3-101 with other anticancer agents.

Haematology, coagulation and biochemistry:
6. Inadequate bone marrow function: 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 if no 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. Serum pregnancy test 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 or 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 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 (CHF);
•Cardiac arrhythmia, except stable atrium fibrillations;
15. Left Ventricle Ejection Fraction (LVEF) by MUGA or ECHO < 50%.
16. Known hypersensitivity to any of the study drug components or its excipie

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To determine the response of 2B3-101 treatment in patients with LM from breast cancer using the LM response score. ;Secondary Objective: -To determine the safety profile <br>-To determine CNS progression free survival <br>-To correlate the clinical and radiological findings (MRI) and CSF cytology with free doxorubicin levels in CSF and in plasma <br>-To determine systemic progression free survival <br>-To determine overall survival <br>-To explore the change in number of CTCs in CSF and blood and correlate this with the LM response score<br>-To explore the change in number of CTCs in CSF and blood and correlate this with free doxorubicine CSF and plasma levels<br>-To determine efficacy of 2B3-101 in patients with breast cancer and LM with the individual components of the primary end points.<br>;Primary end point(s): tumor responce;Timepoint(s) of evaluation of this end point: Every two cycles

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): 1- adverse events<br>2- CNS PFS<br>3- comparisson of clinical, radiological, patological responce and PK levels in CSF and plasma<br>4- systemic PFS<br>5- OS<br>6- change in CTCs in CSF and blood<br>;Timepoint(s) of evaluation of this end point: 1- weekly visit<br>2- every 2 cycles<br>3- every 2 cycles<br>4- systemic PFS<br>5- monthly follow up<br>6- every 2 cycles

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