Phase II trial of intravenous lobradimil and carboplatin in childhood brain tumors: a report from the Children's Oncology Group.
ABSTRACT [corrected] Lobradimil is a synthetic bradykinin analog that rapidly and transiently increases the permeability of the blood-brain barrier (BBB). The combination of lobradimil and carboplatin was studied in pediatric patients with primary brain tumors in a phase II trial, the primary endpoints of which were to estimate the response rate and time to disease progression.
Patients were stratified by histology into five cohorts: brainstem glioma, high-grade glioma, low-grade glioma, medullobastoma/primitive neuroectodermal tumor (PNET), and ependymoma. Patients received carboplatin adaptively dosed to achieve a target AUC of 3.5 mg min/ml per day (7 mg.min/ml/cycle) intravenously over 15 min on 2 consecutive days and lobradimil 600 ng/kg ideal body weight/day on 2 consecutive days each 28 day cycle.
Forty-one patients, age 2-19 years, were enrolled; 38 patients, including 1 patient ultimately determined to have atypical neurocytoma, were evaluable for response. No objective responses were observed in the brainstem glioma (n=12) and high-grade glioma (n = 9) cohorts, although two patients with high-grade glioma had prolonged disease stabilization (>6 months). The study was closed for commercial reasons prior to achieving the accrual goals for the ependymoma (n = 8), medulloblastoma/PNET (n = 6) and low-grade glioma (n = 2) cohorts, although responses were observed in 1 patient with PNET and 2 patients with ependymoma.
The combination of lobradimil and carboplatin was inactive in childhood high-grade gliomas and brainstem gliomas.
- SourceAvailable from: Stanislaw R Burzynski[Show abstract] [Hide abstract]
ABSTRACT: Brainstem gliomas (BSG) are relatively rare tumors of which recurrent pediatric diffuse intrinsic pontine gliomas (RPDIPG) comprise a distinct group. Numerous trials have been conducted on RPDIPG, none of which have resulted in identifying any proven pharmacological treatment benefit. This study included 40 patients diagnosed with different types of BSG, but it was decided to describe first the encouraging results in the most challenging group of RPDIPG. This single-arm phase II study evaluated the efficacy and safety of the combination of antineoplastons A10 and AS2-1 (ANP) in patients with RPDIPG. Seventeen patients (median age 8.8 years) were enrolled, and all were diagnosed with RPDIPG. ANP was administered intravenously daily. Efficacy analyses were conducted in this group of patients. In this group, complete responses were observed in 6 % of patients, partial responses in 23.5 %, and stable disease in 11.8 %. Six-month progression-free survival was 35.3 %. One-year overall survival was 29.4 %, 2 years 11.8 %, and 5, 10, and 15 years 5.9 %. One patient with DIPG is alive over 15 years post-treatment. Grade 3 and higher toxicities including hypokalemia and fatigue occurred in 6 %, hypernatremia in 18 %, fatigue and urinary incontinence in 6 %, and somnolence in 12 %. In a single patient, grade 4 hypernatremia occurred when he was on mechanical ventilation. He was disconnected from the ventilator and died from brain tumor according to the attending physician. Responding patients experienced improved quality of life. The results suggest that ANP shows efficacy and acceptable tolerability profile in patients with RPDIPG.Child s Nervous System 04/2014; · 1.24 Impact Factor
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ABSTRACT: Introduction: Currently, there are many novel drugs that belong to class III or IV of the Biopharmaceutics Classification System, showing low bioavailability. Tight junction (TJ) modulation offers an approach to increase bioavailability of pharmaceutical compounds. Furthermore, some diseases are accompanied by disturbed barrier function or TJ dysregulation and thus represent a second application for TJ modulators. Areas covered: This review contains a summary of three different TJ modulators: AT1002, PN159 and labradimil. Within this summary, the authors provide a description of their effects on TJs, their adverse effects and their success in clinical trials. Furthermore, the authors present the current understanding of TJ regulation and highlight opportunities to develop new TJ modulators; they also review the problems that might occur. Expert opinion: The development of new mechanism-based (MB) TJ modulators is a very promising field of research. MB approaches are expected to have the best future prospects. Further elucidation of signaling pathways and TJ regulation will be necessary for advancing MB TJ modulator research.Expert Opinion on Drug Discovery 02/2014; · 2.30 Impact Factor
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ABSTRACT: Gliomas are the most common malignant brain tumors in adults. Bradykinin (BK) displays an important role in cancer, although the exact role of kinin receptors in the glioma biology remains unclear. This study investigated the role of kinin B1 and B2 receptors (B1R and B2R) on cell proliferation in human glioblastoma cell lineages. The mRNA expression of B1R and B2R was verified by RT-qPCR, whereas the effects of kinin agonists (des-Arg(9)-BK and BK) were analyzed by cell counting, MTT assay and annexin-V/PI determination. The PI3K/Akt and ERK1/2 signaling activation was assessed by flow cytometry. Our results demonstrated that both human glioblastoma cell lines U-138MG and U-251MG express functional B1R and B2R. The proliferative effects induced by the incubation of des-Arg(9)-BK and BK are likely related to the activation of PI3K/Akt and ERK 1/2 pathways. Moreover, the pre-incubation of the selective PI3Kγ blocker AS252424 markedly prevented kinin-induced AKT phosphorylation. Noteworthy, the selective B1R and B2R antagonists SSR240612 and HOE-140 were able to induce cell death of either lineages, with mixed apoptosis/necrosis characteristics. Taken together, the present results show that activation of B1R and B2R might contribute to glioblastoma progression in vitro. Furthermore, PI3K/Akt and ERK 1/2 signaling may be a target for adjuvant treatment of glioblastoma with a possible impact on tumor proliferation.Journal of Neuro-Oncology 07/2014; · 3.12 Impact Factor