A Phase 1b, Open-Label, Study of a Novel Targeted Radiotherapy in Children, Adolescents and Young Adults with Inoperable Relapsed or Refractory High Grade Glioma

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ABSTRACT There is no known cure for pediatric high grade gliomas (HGGs), meaning all patients eventually progress and the prognosis for patients is very poor with 5 year overall survival below 20%. There is a high unmet need for new drugs, including targeted radiopharmaceuticals, preferably with the ability to cross the blood-brain barrier and have cancer-specific uptake, as there are no FDA approved treatments in either the 1st or 2nd line or relapsed/refractory (r/r) setting at this time. These children are frequently treated off-label with drugs approved for similar adult indications with little to no data to support the use in a pediatric HGG population, or are restricted to investigational agents within clinical trials. CLR 131 is a radio-iodinated therapy comprising a core phospholipid ether (PLE) analogue, 18-(p-iodophenyl)octadecyl phosphocholine, radiolabeled with iodine-131. The cancer cell-selective uptake of PLEs and related lipids involves the selective insertion into lipid rafts. Malignant cells have far greater amounts of lipid rafts than normal cells and these lipid rafts spatially organize signalling pathways and regulate cell proliferation and survival. CLR 131 exploits the tumor-targeting properties of PLEs to provide a targeted delivery of radiation to malignant tumor cells and minimizes radiation exposure to normal tissues. Additionally, PLEs and CLR 131 have demonstrated the ability to cross the blood-brain barrier and provide sufficient uptake into CNS tumors to result in improvements in progression free survival, overall survival and response rates. CLR 131 was identified from a series of PLEs as the optimal delivery agent in rodent models. Iodine-131 was chosen as the radioactive constituent due to its eight-day half-life and well-established therapeutic capabilities in multiple adult and pediatric cancer types. The therapeutic hypothesis for CLR 131 is supported by data from nonclinical studies using in vitro cancer cell lines as well as in vivo tumor bearing murine models which include neuroblastoma, several soft tissue sarcomas and hematologic malignancies. To date, over 150 adult and pediatric patients with advanced r/r cancers have received CLR 131, as part of Phase 1 and 2 clinical trials in different types of cancers (including solid and hematological cancers), demonstrating that CLR 131 provides significant inhibition of tumor growth and an overall survival benefit over control groups. We are proposing a multi-center, open-label, Phase 1b dose finding study evaluating intravenous administration of CLR 131 in up to 25 children, adolescents and young adults with recurrent or refractory malignant HGG at two doses (25 children per dose group). We predict that CLR 131, in this expanded pediatric population study, will have a similar safety profile as was observed in pediatric and adult patients with cancer dosed at similar levels. The planned next step is a pivotal Phase 2/3 study to evaluate the efficacy of CLR 131 in children, adolescents and young adults with recurrent or refractory malignant HGG.