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NTOX-09. RECOMMENDED PHASE II DOSE OF INTRA-ARTERIAL MELPHALAN GIVEN WITH INTRA-ARTERIAL CARBOPLATIN, OSMOTIC BLOOD-BRAIN BARRIER DISRUPTION AND DELAYED OTOPROTECTIVE SODIUM THIOSULFATE FOR PATIENTS WITH RECURRENT OR PROGRESSIVE CNS EMBRYONAL OR GERM CELL TUMORS

ABSTRACT: Abstract INTRODUCTION Intra-arterial chemotherapy in conjunction with transient osmotic BBB disruption (IA/BBBD) has been shown to increase drug delivery (10-100 folds) to the CNS. We report the maximum tolerated dose of IA melphalan in combination with IA carboplatin with BBBD and delayed IV sodium thiosulfate (STS) otoprotection for patients with recurrent or progressive CNS embryonal or germ cell tumors. In Prior studies, STS has been shown to protect against carboplatin-induced hearing loss. METHODS This prospective single-institution phase I/II trial was approved by the institutional review board (NCT00983398). Subjects with embryonal and germ cell tumors of the CNS between 1 and 45 years of age, and met the inclusion/exclusion criteria received IA carboplatin (200 mg/m2/day x two days) and melphalan (starting at 4 mg/m2 x two days with inter-patient 3X3 dose escalation as per protocol until the MTD was reached) in conjunction with osmotic BBBD on two consecutive days every 4-6 weeks for up to 12 treatment cycles. For otoprotection, IV STS was given four and eight hours after carboplatin. RESULTS 10 males and 4 females (median age 16.3 years, 1.7-28.6 yrs) were enrolled. 11/14(79%) had objective radiographic responses (4 PR, 7 SD). Most frequent grade 3 or 4 toxicities were hematological (64%) with only 1/14 patients developing ototoxicity (Brock’s grade-4). The maximum tolerated dose of IA Melphalan was 6 mg/ m2 x 2 days. CONCLUSION The recommended dose phase II dose of melphalan is 6 mg/m2 IA x 2 days when given with IA carboplatin administered with BBBD and delayed IV STS for otoprotection. Favorable safety profile, objective responses and excellent hearing protection compared to IA/BBBD carboplatin without STS warrants proceeding with the phase II part of this study. Phase I study will continue for subjects younger than 10 years due to limited accrual in this age group.

SUBMITTER: Ambady P

PROVIDER: S-EPMC5693116 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Project description:Abstract BACKGROUND: In previous work we established that PLK4 is overexpressed and essential for proliferation and survival of pediatric embryonal brain tumors. PLK4 is a cell cycle-regulated protein recruited at the centrosome in dividing cells. Its overexpression triggers centrosome amplification, which is associated with genetic instability and carcinogenesis. We demonstrated that PLK4 inhibition exerts a potent cytostatic effect in EBT. We also established the synergism of the PLK4 inhibitor CFI-400945 with cytotoxic drugs and other signal transduction modulators. METHODS: We studied protein kinase inhibitors (PKI) with PLK4 cross-over potential (CFI-400945, CFI-400437, centrinone, centrinone-B, R-1530, axitinib, alisertib and KW-2449) by assessing their chemical profiles through docking simulations over PLK4 (PDB entry: 3COK) using Gold 5.4 software; evaluating their potential to penetrate the BBB (via logBB calculation by Clark equation), performing LanthaScreen EU Kinase Binding assays (ThermoFisher Scientific) and cell based studies (viability and proliferation) in multiple embryonal tumor cell lines (MON, BT-12, BT-16, DAOY, D283). RESULTS: Kinase binding assays and cell based studies showed that CFI-400437 was the most effective compound, yielding an IC50 <5nM in the binding assay and requiring <100nM of drug to significantly inhibit proliferation in multiple cell lines. However, docking simulations using the PLK4 catalytic cavity and each of the various PKIs demonstrated that all of the inhibitors tested exhibit similar interactions within the binding cavity, engaging in H-bonding with backbone residues Glu-89 and Cys-91. Additional polar and hydrophobic (?-stacking) interactions were also identified for each of the PKIs. LogBB calculations revealed that compound R-1530 has the greatest likelihood to enter the brain (LogBB+0.130). CONCLUSION: Although CFI-400945 is the most effective PLK4 inhibitor among those assayed, it has low potential for BBB exposure. Molecular docking results indicate the potential to develop new chemical entities with higher BBB exposure potential using a similar binding mode to that of CFI-400945.

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NTOX-09. RECOMMENDED PHASE II DOSE OF INTRA-ARTERIAL MELPHALAN GIVEN WITH INTRA-ARTERIAL CARBOPLATIN, OSMOTIC BLOOD-BRAIN BARRIER DISRUPTION AND DELAYED OTOPROTECTIVE SODIUM THIOSULFATE FOR PATIENTS WITH RECURRENT OR PROGRESSIVE CNS EMBRYONAL OR GERM CELL TUMORS

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