Abstract
Chemotherapy is a very frequently used therapy in patients with advanced tumors with or without central nervous system (CNS) metastases or primary brain tumors. Despite the significant progress in drug development, the survival of patients is limited with an unmet need for more effective chemotherapeutics that have an acceptable safety
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profile. This thesis presents I/II clinical phase studies with an aim to investigate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and the preliminary anti-tumor activity of novel anti-cancer drugs or new combinations of drugs already in use. During the research we were able to recommend dosing schedules and dose-levels of the (combination of) drug(s) for further clinical studies and confirmed drug-drug interactions or food-effects. The second part of this thesis presents pharmaceutical/nanomedicine strategies and laboratory assays in the treatment, diagnosis and drug-monitoring of central nervous system (CNS) tumors. We represent the review of the literature that discusses new drug strategies of targeting blood-brain barrier (BBB) by active chemo- and immunotherapies. Due to the presence of the blood-brain barrier (BBB) only few systemic drugs can be used to treat brain tumors. As treatment of systemically metastasized cancer patients becomes more effective and prolongs patient’s survival, CNS metastases are more frequently observed. Recently, using nanotechnology active chemotherapeutics can be safely transported across the barriers (BBB and blood-cerebrospinal fluid barrier (BCSFB)) and target brain and CSF, respectively. Further studies on improving the brain-penetration of potentially effective drugs for brain tumors is warranted. In the line with this we describe two clinical studies with a novel strategy consisting of administration of glutathione liposomal PEGylated doxorubicin (2B3-101) as a treatment of patients with solid tumors and brain metastases or recurrent malignant glioma and leptomeningeal metastases from breast cancer. Doxorubicin is a well- known, frequently used chemotherapeutic agent in various tumor types, such as breast cancer and lung cancer. Glioblastoma cell lines showed to be sensitive to doxorubicin, however, without the carrier, doxorubicin cannot pass the BBB. The first study with 2B3-101 demonstrated that treatment of patients with solid tumors and brain metastases or malignant gliomas with 2B3-101 showed a dose-dependent PK profile and is safe and relatively well tolerated with both as single agent and with trastuzumab co-administration. Intracranial and extracranial preliminary anti-tumor activity was observed in patients with (HER2+) breast cancer with brain metastases and malignant glioma. In the second study using 2B3-101 in patients with leptomeningeal metastases (LM) from breast cancer, doxorubicin concentrations in the CSF were within the reported IC50, a measure of effectiveness in-vitro in two out of three patients. One of the three treated patients with LM showed stable disease for 10 cycles and progression free survival for more than six months. Further we demonstrate the clinical application of the circulating tumor cell assay (CTC) for EPCAM-positive cells (an epithelial tumor cell marker) to be more sensitive in diagnosing leptomeningeal metastases in CSF (100%), than the standard CSF cytology method (71%) in patients with clinically suspected LM or with already diagnosed LM, while both methods showed a very high specificity (100%).
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