Phase I Amount
$1,034,797
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.
Public Health Relevance Statement: NARRATIVE Most pediatric patients with relapsed high grade glioma are confronted with a poor prognosis. For these patients there is currently no accepted second-line treatment regimen. There is a need for new drugs, including targeted radiopharmaceuticals, preferably with the ability to cross the blood-brain barrier and provide cancer-specific uptake.
Project Terms: Advanced Cancer; Advanced Malignant Neoplasm; Cell Membrane Lipid Rafts; Sphingolipid Microdomains; Sphingolipid-Cholesterol Rafts; lipid raft; Membrane Microdomains; Magnetic Resonance Imaging Scan; MRI Scans; Phase I Clinical Trials; Early-Stage Clinical Trials; Phase 1 Clinical Trials; phase I protocol; Normal Cell; Radio; Childhood Neoplasm; Childhood Tumor; Pediatric Tumor; tumors in children; Pediatric Neoplasm; Dose; Data; Radioactive; Subgroup; in vivo; Enrollment; enroll; External Beam Radiation Therapy; Definitive Radiation Therapy; EBRT; External Beam RT; External Radiation; external-beam radiation; Rodent Model; Xenograft Model; xenograft transplant model; xenotransplant model; Monitor; Radiolabeled; Development; developmental; Image; imaging; open label; open label study; preclinical study; pre-clinical study; virtual; efficacy evaluation; efficacy analysis; efficacy assessment; efficacy examination; evaluate efficacy; examine efficacy; Childhood Glioma; Pediatric Glioma; Pediatric high-grade glioma; Treatment Efficacy; intervention efficacy; therapeutic efficacy; therapy efficacy; targeted delivery; site targeted delivery; Cancer cell line; Population; cancer type; chemotherapy; novel therapeutics; new drug treatments; new drugs; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel therapy; mouse model; murine model; tumor; novel therapeutic intervention; new therapeutic approach; new therapeutic intervention; new therapeutic strategies; new therapy approaches; novel therapeutic approach; novel therapeutic strategies; novel therapy approach; FDA approved; treatment response; response to therapy; response to treatment; therapeutic response; therapy response; standard care; standard treatment; arm; Adolescent and Young Adult; pediatric patients; child patients; targeted agent; Soft tissue sarcoma; Radiation exposure; radiological imaging; Radiography; Roentgenography; radiologic imaging; clinical development; secondary endpoint; secondary end point; primary endpoint; primary end point; radiation delivery; appropriate dose; optimal drug dosage; optimal drug dose; Phase Ib Clinical Trial; Phase 1b Clinical Trial; targeted radiotherapeutic; Prognosis; patient prognosis; Adult; 21+ years old; Adult Human; adulthood; Blood - brain barrier anatomy; Blood-Brain Barrier; Hemato-Encephalic Barrier; bloodbrain barrier; Brain; Brain Nervous System; Encephalon; Brain Neoplasms; Brain Neoplasia; Brain Tumors; tumors in the brain; Malignant Neoplasms; Cancers; Malignant Tumor; malignancy; neoplasm/cancer; Malignant neoplasm of thyroid; Malignant Thyroid Gland Neoplasm; Malignant Tumor of the Thyroid; Malignant Tumor of the Thyroid Gland; Thyroid Cancer; Cell Survival; Cell Viability; Child; 0-11 years old; Child Youth; Children (0-21); youngster; Clinical Research; Clinical Study; Clinical Trials; Control Groups; Disease; Disorder; intravenous administration; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Glioma; Glial Cell Tumors; Glial Neoplasm; Glial Tumor; Neuroglial Neoplasm; Neuroglial Tumor; glial-derived tumor; neuroglia neoplasm; neuroglia tumor; Half-Life; Primary carcinoma of the liver cells; Hepatocarcinoma; Hepatocellular Carcinoma; Hepatocellular cancer; Hepatoma; Liver Cells Carcinoma; liver carcinoma; In Vitro; Lipids; Non-Hodgkin's Lymphoma; Nonhodgkins Lymphoma; non-Hodgkins disease; Morbidity - disease rate; Morbidity; Neuroblastoma; Patients; Ether Phosphatidates; Glycerol Phosphate Ethers; Glycerophosphate Ethers; Phospholipid Ethers; Choline Chloride Dihydrogen Phosphate; Choline Phosphate; Choline Phosphate Chloride; Phosphocholine; Phosphorylcholine Chloride; Phosphorylcholine; Response RT; Response Time; psychomotor reaction time; Reaction Time; Recurrent; Recurrence; Relapse; Risk; Safety; Signal Pathway; Testing; Time; Tissues; Body Tissues; single photon emission computed tomography; SPECT; SPECT imaging; Single-Photon Emission-Computed Radionuclide Tomography; X-Ray Computed Tomography; CAT scan; CT X Ray; CT Xray; CT imaging; CT scan; Computed Tomography; Tomodensitometry; X-Ray CAT Scan; X-Ray Computerized Tomography; Xray CAT scan; Xray Computed Tomography; Xray computerized tomography; catscan; computed axial tomography; computer tomography; computerized axial tomography; computerized tomography; non-contrast CT; noncontrast CT; noncontrast computed tomography; Treatment Protocols; Treatment Regimen; Treatment Schedule; Central Nervous System Neoplasms; CNS Tumor; CNS neoplasm; Central Nervous System Tumors; tumors in the central nervous system; base; Label; Radiopharmaceuticals; Radiopharmaceutical Compound; radioactive drugs; radiotherapeutic drugs; Peripheral; Solid; Clinical; Refractory; Malignant - descriptor; Malignant; Microscopic; Phase; Medical; Series; Targeted Radiotherapy; Evaluation; Lesion; Surgical margins; pediatric; Childhood; Progression-Free Survivals; Event-Free Survival; Disease-Free Survival; analog; uptake; Childhood Cancers; Malignant Childhood Tumor; Malignant Pediatric Neoplasm; Malignant Pediatric Tumor; Malignant childhood cancer; cancer in a child; cancer in children; child with cancer; childhood malignancy; children with cancer; pediatric cancer; pediatric malignancy; Malignant Childhood Neoplasm; Phase 2 Clinical Trials; phase II protocol; Phase II Clinical Trials; Therapeutic; 131 Iodine; I-131; Iodine I 131; I131 isotope; Exposure to; Normal Tissue; Normal tissue morphology; Malignant Cell; cancer cell; Venous; Diagnostic; Nature; Hematologic Cancer; Hematologic Malignancies; Hematological Malignancies; Hematological Neoplasms; Hematological Tumor; Hematopoietic Cancer; Malignant Hematologic Neoplasm; Hematologic Neoplasms; Investigation; Scanning; Tumor Volume; Cell Growth in Number; Cell Multiplication; Cellular Proliferation; Cell Proliferation; Tumor Cell; neoplastic cell; tumor growth; dosimetry; novel; population-based study; population-level study; studies of populations; study of the population; Population Study; Abscission; Extirpation; Removal; Surgical Removal; resection; Excision; Property; response
