Novel systemic treatment options for advanced solid tumors with or without central nervous system metastases or malignant glioma

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 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%)

Novel systemic treatment options for advanced solid tumors with or without central nervous system metastases or malignant glioma

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 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%)

Strategies to target drugs to gliomas and CNS metastases of solid tumors

The treatment for central nervous system metastases of solid tumors and gliomas is limited as the blood–brain barrier (BBB) is an obstacle to systemic therapy. Here, we review the physiochemical properties of the BBB and both current and new drug strategies to penetrate brain tumors. We focus on targeting receptor- or carrier-mediated transport mechanisms over the BBB used by drug conjugates, nanoparticles, polymer-based nanocarriers, siRNA, and antibodies

EpCAM-based flow cytometry in cerebrospinal fluid greatly improves diagnostic accuracy of leptomeningeal metastases from epithelial tumors

BACKGROUND: Moderate diagnostic accuracy of MRI and initial cerebrospinal fluid (CSF) cytology analysis results in at least 10%-15% false negative diagnoses of leptomeningeal metastases (LM) of solid tumors, thus postponing start of therapy. The aim of this prospective clinical study was to determine the diagnostic value of epithelial cell adhesion molecule (EpCAM)-based flow cytometry versus cytology in CSF for the diagnosis of LM in patients with epithelial tumors. METHODS: Patients with a clinical suspicion of LM but a negative or inconclusive MRI in whom a diagnostic lumbar puncture has to be performed were included. At least 5 mL of CSF for cytology, 5 mL for flow cytometry, 2 mL for cell count and biochemistry, and 8 mL whole blood samples for circulating tumor cells measurements and biochemistry were drawn. Tumor cells in CSF and whole blood were detected by multiparameter flow cytometry using EpCAM antibody. RESULTS: In total 29 eligible patients were enrolled in the study. Thirteen patients were ultimately diagnosed with LM. The flow cytometry assay showed 100% sensitivity and 100% specificity for diagnosing LM, while sensitivity of CSF cytology was only 61.5%. Cell count or biochemical parameters in CSF were abnormal in 100% of patients with LM. CONCLUSIONS: Our results suggest that the EpCAM-based flow cytometry assay is superior to CSF cytology for the diagnosis of LM in patients with an epithelial tumor, a clinical suspicion of LM, and a nonconclusive MRI. Confirmation of these data is needed in a larger dataset to recommend dual CSF diagnostics for LM. CLINICALTRIALSGOV IDENTIFIER: NCT01713699

A phase I, dose escalation, pharmacodynamic, pharmacokinetic, and food-effect study of α2 integrin inhibitor E7820 in patients with advanced solid tumors

E7820 is an orally administered sulfonamide that inhibits alfa-2-integrin mRNA expression. Pre-clinically E7820 showed tumor anti-angiogenic effects in various tumor cell lines and xenograft mouse models. Human daily dosing of 100 mg QD had previously been shown to be safe and tolerable. Methods The study consisted of two parts: Part A (food effect) and Part B (determination of maximum tolerated dose (MTD) for bi-daily (BID) dosing). E7820 dosing started at 50 mg BID with planned escalation to 60, 80 and 100 mg BID every 28 days. Results Fifteen patients were enrolled in Part A and 26 in Part B. The most frequent adverse events of all grades were constipation, diarrhea, nausea, and fatigue while anemia, neutropenia, and fatigue were most frequent grade ≥3 toxicities. At dose-level 60 mg BID, two patients experienced dose-limiting toxicities (grade 3 neutropenic sepsis and grade 4 neutropenia). Therefore the recommended dose (RD) was 50 mg BID. Food had no effect on E7820 exposure. E7820 exposure following twice daily administration was dose-proportional. Expression of platelet integrin-α2 measured as a response biomarker in Part B, generally decreased by a median 7.7 % from baseline following treatment with 50 mg BID E7820. Reduction was most pronounced within 1-week post treatment. The median duration of treatment was median 54, range 20–111 days. The best overall response in any treatment group was stable disease (SD): 23.1 % in Part A (100 mg QD); at the RD 66.7 % (12 of 18 patients) and 40 % in the 60 mg BID group in Part B. Conclusions:Food had no effect on E7820 exposure. A dose of 50 mg BID was considered the MTD. Treatment with E7820 is safe and tolerable with 2/3 of patients (66.7 %) at MTD having SD as their best response

Angiotensin II-Receptor Inhibition With Candesartan to Prevent Trastuzumab-Related Cardiotoxic Effects in Patients With Early Breast Cancer: A Randomized Clinical Trial

IMPORTANCE: This is the first randomized placebo-controlled evaluation of a medical intervention for the prevention of trastuzumab-related cardiotoxic effects. OBJECTIVE: To determine as the primary end point whether angiotensin II antagonist treatment with candesartan can prevent or ameliorate trastuzumab-related cardiotoxic effects, defined as a decline in left ventricular ejection fraction (LVEF) of more than 15% or a decrease below the absolute value 45%. DESIGN: This randomized, placebo-controlled clinical study was conducted between October 2007 and October 2011 in 19 hospitals in the Netherlands, enrolling 210 women with early breast cancer testing positive for human epidermal growth factor receptor 2 (HER2) who were being considered for adjuvant systemic treatment with anthracycline-containing chemotherapy followed by trastuzumab. INTERVENTIONS: A total of 78 weeks of candesartan (32 mg/d) or placebo treatment; study treatment started at the same day as the first trastuzumab administration and continued until 26 weeks after completion of trastuzumab treatment. MAIN OUTCOMES AND MEASURES: The primary outcome was LVEF. Secondary end points included whether the N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hs-TnT) can be used as surrogate markers and whether genetic variability in germline ERBB2 (formerly HER2 or HER2/neu) correlates with trastuzumab-related cardiotoxic effects. RESULTS: A total of 206 participants were evaluable (mean age, 49 years; age range, 25-69 years) 103 in the candesartan group (mean age, 50 years; age range, 25-69 years) and 103 in the placebo group (mean age, 50 years; age range, 30-67 years). Of these, 36 manifested at least 1 of the 2 primary cardiac end points. There were 3.8% more cardiac events in the candesartan group than in the placebo group (95% CI, -7% to 15%; P = .58): 20 events (19%) and 16 events (16%), respectively. The 2-year cumulative incidence of cardiac events was 0.28 (95% CI, 0.13-0.40) in the candesartan group and 0.16 (95% CI, 0.08-0.22) in the placebo group (P = .56). Candesartan did not affect changes in NT-proBNP and hs-TnT values, and these biomarkers were not associated with significant changes in LVEF. The Ala1170Pro homozygous ERBB2 genotype was associated with a lower likelihood of the occurrence of a cardiac event compared with Pro/Pro + Ala/Pro genotypes in multivariate analysis (odds ratio, 0.09; 95% CI, 0.02-0.45; P = .003). CONCLUSIONS AND RELEVANCE: The findings do not support the hypothesis that concomitant use of candesartan protects against a decrease in left ventricular ejection fraction during or shortly after trastuzumab treatment in early breast cancer. The ERBB2 germline Ala1170Pro single nucleotide polymorphism may be used to identify patients who are at increased risk of trastuzumab-related cardiotoxic effects. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00459771

Angiotensin II-Receptor Inhibition With Candesartan to Prevent Trastuzumab-Related Cardiotoxic Effects in Patients With Early Breast Cancer:A Randomized Clinical Trial

IMPORTANCE This is the first randomized placebo-controlled evaluation of a medical intervention for the prevention of trastuzumab-related cardiotoxic effects. OBJECTIVE To determine as the primary end point whether angiotensin II antagonist treatment with candesartan can prevent or ameliorate trastuzumab-related cardiotoxic effects, defined as a decline in left ventricular ejection fraction (LVEF) of more than 15% or a decrease below the absolute value 45%. DESIGN This randomized, placebo-controlled clinical study was conducted between October 2007 and October 2011 in 19 hospitals in the Netherlands, enrolling 210 women with early breast cancer testing positive for human epidermal growth factor receptor 2 (HER2) who were being considered for adjuvant systemic treatment with anthracycline-containing chemotherapy followed by trastuzumab. INTERVENTIONS A total of 78 weeks of candesartan (32mg/d) or placebo treatment; study treatment started at the same day as the first trastuzumab administration and continued until 26 weeks after completion of trastuzumab treatment. MAIN OUTCOMES AND MEASURES The primary outcome was LVEF. Secondary end points included whether the N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hs-TnT) can be used as surrogate markers and whether genetic variability in germline ERBB2 (formerly HER2 or HER2/neu) correlates with trastuzumab-related cardiotoxic effects. RESULTS A total of 206 participants were evaluable (mean age, 49 years; age range, 25-69 years) 103 in the candesartan group (mean age, 50 years; age range, 25-69 years) and 103 in the placebo group (mean age, 50 years; age range, 30-67 years). Of these, 36 manifested at least 1 of the 2 primary cardiac end points. Therewere 3.8% more cardiac events in the candesartan group than in the placebo group (95% CI, -7% to 15%; P=.58): 20events (19%) and 16 events (16%), respectively. The 2-year cumulative incidence of cardiac events was 0.28 (95% CI, 0.130.40) in the candesartan group and 0.16 (95% CI, 0.08-0.22) in the placebo group (P=.56). Candesartan did not affect changes in NT-proBNP and hs-TnT values, and these biomarkers were not associated with significant changes in LVEF. The Ala1170Pro homozygous ERBB2 genotype was associated with a lower likelihood of the occurrence of a cardiac event compared with Pro/Pro + Ala/Pro genotypes in multivariate analysis (odds ratio, 0.09; 95% CI, 0.02-0.45; P=.003). CONCLUSIONS AND RELEVANCE The findings do not support the hypothesis that concomitant use of candesartan protects against a decrease in left ventricular ejection fraction during or shortly after trastuzumab treatment in early breast cancer. The ERBB2 germline Ala1170Pro single nucleotide polymorphism may be used to identify patients who are at increased risk of trastuzumab-related cardiotoxic effects

Phase i and pharmacological study of pazopanib in combination with oral topotecan in patients with advanced solid tumours

Background: This phase I study evaluated the safety, tolerability, maximum tolerated dose (MTD) and pharmacokinetics of two dosing schedules of oral topotecan in combination with pazopanib in patients with advanced solid tumours. Methods: Stage I of this study was to determine whether there was an impact of pazopanib on topotecan exposure. In stage II, the MTD and safety profile of oral topotecan given weekly on days 1, 8 and 15 in a 28-day cycle; or daily-times-five on days 1-5 in a 21-day cycle, both in combination with daily pazopanib, were explored. Results: In total, 67 patients were enroled. Pazopanib co-administration caused a substantial increase in exposure to total topotecan (1.7-fold) compared with topotecan alone, which is considered clinically relevant. Topotecan had no effect on pazopanib concentrations. Safety findings were consistent with the known profile of both agents. There were three drug-related deaths, liver failure, tumour haemorrhage and myelosuppression. Two patients experienced dose-limiting toxicities (DLTs; hand-foot syndrome, myelosuppression and diarrhoea) on the weekly topotecan schedule and four patients experienced DLTs (myelosuppression) on the daily-times-five topotecan schedule. When combined with pazopanib, 800 mg daily, the recommended doses for oral topotecan are: 8 mg weekly and 2.5 mg daily-times-five. Seven of eight patients with partial response had platinum-resistant ovarian cancer. In addition, 54% of patients had stable disease with 22% stable for 6 months. Conclusions: Total topotecan exposure is 1.7-fold higher when co-administered with pazopanib. Both schedules of administration were tolerated and would permit further evaluation, especially the weekly schedule