• John L Gainer, Jason P Sheehan, James M Larner, and David R Jones.
• Diffusion Pharmaceuticals LLC;
• J. Neurosurg. 2017 Feb 1; 126 (2): 460-466.

AbstractOBJECTIVE A new drug, trans sodium crocetinate (TSC), has been developed to enhance the delivery of oxygen to hypoxic tissues. Cancerous tumors, such as glioblastoma multiforme (GBM), are very hypoxic, and it has been suggested that radiation therapy (RT) is more beneficial if tumors are better oxygenated. A Phase I/II clinical trial was conducted to determine the effect of adding TSC to RT sessions. METHODS An open, single-arm clinical trial incorporating the standard of care (SOC) for GBM was conducted at 18 clinical sites. There were 6 weeks of RT consisting of 2 Gy/day for 5 days/week, beginning after an initial resection or stereotactic biopsy to confirm GBM. Temozolomide (TMZ), 75 mg/m2, was given before each RT session. The TSC, 0.25 mg/kg, was intravenously administered around 45 minutes before an RT session 3 days/week, usually on Monday, Wednesday, and Friday. A Phase I run-in period included 2 cohorts. The first cohort contained 3 patients who were given a half dose of the intravenous TSC (that is, 0.25 mg/kg, 3 times per week for only the first 3 weeks of RT). After a Safety Monitoring Committee (SMC) had verified that no dose-limiting toxicity (DLT) had occurred, a second cohort of 6 patients was given the same dosage of TSC but for the full 6 weeks of RT. After the SMC verified that no DLTs had occurred, Phase II began, with the administration of the full 18 doses of TSC. Fifty additional patients were enrolled during Phase II. Following the completion of RT, the patients rested for a month. After that, SOC TMZ chemotherapy (150-200 mg/m2) was administered for 5 days of the 1st week of 6 monthly cycles. No TSC was administered during this chemotherapy phase or later in the trial. Any other follow-up therapies were administered at the discretion of the individual investigators. RESULTS Kaplan-Meier analysis showed that 36% of the full-dose TSC patients were alive at 2 years, compared with historical survival values ranging from 27% to 30% for the SOC. Survival for the biopsy-only subset of patients was 40%, as compared with 42.9% for those patients having a complete resection before treatment. In addition, 2 of the 3 Phase I, Cohort 1 patients survived at 2 years. Contrast MRI data suggested that considerable pseudoprogression had occurred. Both Karnofsky Performance Status (KPS) scores and quality of life (QOL) questionnaires indicated that a good quality of life existed for most patients throughout the trial. No serious adverse events occurring in the trial were attributed to TSC. CONCLUSIONS This trial contained a single arm consisting of 59 patients. The results strongly suggested that adding TSC during RT is beneficial for the treatment of GBM. Trans sodium crocetinate offers a novel, easily implemented way to combat hypoxia in tumor tissue. Clinical trial registration no.: NCT01465347 ( clinicaltrials.gov ).

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