A phase Ib/II clinical trial of a novel oxygen therapeutic in chemoradiation of glioblastoma.

Abstract

2561 Background: Tumor hypoxia limits the response of glioblastoma multiforme (GBM) to radiotherapy (RT) and chemotherapy (temozolomide[TMZ]). Additionally, patient biomarkers are strong predictors of responsiveness to TMZ. The purpose of this study is to evaluate the use of a novel oxygen therapeutic, dodecafluoropentane emulsion (DDFPe), in chemoradiation treatment of GBM and stratify the results based on predicted TMZ response. Methods: 11 adult GBM patients have been enrolled. Patients were administered DDFPe via IV infusion (2% w/vol at doses of 0.05, 0.1 or 0.17 mL/kg) an hour prior to each 2 Gy fraction of RT (30 fractions over 6-weeks) with supplemental oxygen. Patients also received standard concurrent and adjuvant TMZ. To confirm tumor re-oxygenation, patients underwent TOLD MRI before and after DDFPe administration. Archived tumor specimens were studied with GliomaSTRAT assay for methylated genes predictive of response. Patients were also studied with serial MRI scans per standard of care and followed for survival. Results: There were minimal acute adverse events related to DDFPe administration. One patient at each of dose levels 0.1 and 0.17 mL/kg developed symptomatic radiation necrosis, which was judged to be related to DDFPe. Enrollment has continued at the 0.1 mL/kg dose without additional significant DDFPe-related toxicity. TOLD MRI showed significant decrease in T1of tumor tissue consistent with tumor re-oxygenation (p=0.015) with no significant change in oxygenation of normal brain tissue. Historically, the average overall survival for GBM patients, for both TMZ responders and non-responders, is about 14.6 months. The progress chart for patient overall survival is listed below, 4 patients have died. All other patients are alive. Conclusions: DDFPe is a promising oxygen therapeutic for reversing tumor hypoxia. A Phase II study is being planned to assess its effectiveness. Clinical trial information: NCT02189109. [Table: see text]

Overcoming tumor hypoxia as a barrier to radiotherapy, chemotherapy and immunotherapy in cancer treatment

“…NVX-108 was tested in an Australian Phase Ib/II dose finding, pharmacodynamic study of NVX-108 combined with radiation and TMZ in patients with newly-diagnosed GBM (NCT02189109). 82 All patients received standard chemoradiation consisting of 30 fractions of focal brain radiation (total 60 Gray, given as 2 Gray fractions, 5 days per week for 6 weeks) with concurrent oral TMZ at a dose of 75 mg/m 2 day, 7 days per week for 6 weeks. NVX-108 was administered by i.v.…”

“…TOLD MRI showed significant decrease in T1 in tumor tissue (P=0.015) with no significant change in normal brain tissue. 82 The Phase Ib/II study consisted of an initial dose exploration phase with a starting dose of 0.05 mL/kg and a dose expansion phase at the MTD of 0.1 mL/kg. An accelerated dose-escalation scheme was employed, using NVX-108 dose levels of 0.05, 0.1, 0.17, 0.25 and 0.35 mL/kg.…”

Sensitization of Hypoxic Tumors to Radiation Therapy Using Ultrasound-Sensitive Oxygen Microbubbles

“…A variety of systemic approaches for overcoming tumor hypoxia immediately prior to therapy have been proposed including hyperbaric chambers, carbogen breathing, erythropoietin injections, and pharmacological agents such as pentoxifylline and nicotinamide to increase blood flow, but these have failed to successfully translate clinically (12–16). More recent research efforts that now target more focused approaches such as pharmacologic respiratory inhibition or oxygen scavengers entrapped within the tumor to inhibit the rate of oxygen consumption (17–19). Ultrasound-sensitive microbubbles containing oxygen (SE61O 2 ) for localized O 2 delivery prior to radiation therapy have been previously proposed by our group (20).…”

In vitro model to compare the oxygen offloading behaviour of dodecafluoropentane emulsion (DDFPe)

“…Sonus Pharmaceuticals licensed the rights for DDFPe to NuvOx Pharma (Tucson, Arizona), which repurposed its development as an oxygen therapeutic for indications such as stroke and TBI, and as a radiosensitizer to treat glioblastoma multiforme (GBM). DDFPe has been tested at doses of 0.05, 0.1, and 0.17 ml/kg (0.001, 0.002, and 0.0034 g DDFP/kg) in a Phase Ib/II clinical trial for GBM [11] and has been shown to be safe in humans at three doses of 0.17 ml/kg administered 90 min apart in a Phase Ib/II trial in acute ischemic stroke patients.…”