Diffusion Pharmaceuticals Inc. opened the phase III INTACT (INvestigating Tsc Against Cancerous Tumors) trial of its lead small molecule, trans sodium crocetinate (TSC), in patients with newly diagnosed inoperable glioblastoma multiforme (GBM), seeking to replicate findings from a phase II study in which a subgroup of inoperable GBM patients showed a nearly four-fold increase in survival at two years compared with historical controls (40 percent vs. 10.4 percent) when TSC was added to their treatment regimen.

The Charlottesville, Va.-based company is using TSC to target cancers in which tumor hypoxia diminishes the effectiveness of existing treatments. A vitamin A analog discovered at the University of Virginia, TSC targets the cancer's hypoxic micro-environment, re-oxygenating treatment-resistant tissue and rendering cancer cells more vulnerable to the therapeutic effects of conventional radiation therapy (RT) and chemotherapy. TSC enhances the diffusion of oxygen to oxygen-deprived tissues by altering the density of plasma. The company is pursuing the thesis that a largely intact GBM tumor vasculature with limited surgical resection is conducive to TSC's tumor re-oxygenation properties, contributing to the survival increase in the GBM inoperable patient subgroup in the phase II study.

The open-label registration trial is expected to screen 300 patients at up to 100 sites in the U.S. and Europe and to enroll 264 to ensure that results from 236 patients will be available for analysis. TSC at doses of 0.25 mg/kg to 1.5 mg/kg in combination with concomitant standard of care (SOC) temozolomide will be assigned in the first eight subjects enrolled in INTACT, who will receive RT plus temozolomide plus TSC (0.25 mg/kg) for six weekly cycles followed by four weeks of rest. At week 10, the same participants will be assigned to treatment, with two subjects each assigned to TSC at doses of 0.25, 0.50, 1.0 and 1.5 mg/kg and studied in parallel for two 28-day cycles with inclusion of appropriate blood sampling collection to assess pharmacokinetics.

The trial's data safety monitoring board (DSMB) will examine safety data after two cycles and may recommend continued use of the 1.5 mg/kg TSC dose during post-radiation temozolomide treatment or prescribe another dose. Subjects then entering INTACT will be randomized 1:1 at baseline into treatment, where they will receive an intravenous bolus of TSC shortly before temozolomide and RT, or a control group where patients will receive SOC alone. TSC will be administered to patients in the treatment arm during both the RT and post-radiation temozolomide periods.

Individuals randomized to treatment will receive TSC 1.5 mg/kg (or another dose if recommended by the DSMB) 1.5 to two hours before temozolomide during the daytime on three days during the first week of each 28-day cycle, with doses on the other two weekdays given at night at home. Long-acting antiemetics may be administered prior to daytime temozolomide dosing.

During the RT treatment period, participants will receive focal RT at 60Gy/30 fractions scheduled at 2Gy/day each weekday for six weeks. Individuals on the treatment arm will receive IV TSC 0.25 mg/kg for three days each week, administered 45 to 60 minutes prior to each RT session. All trial participants will receive temozolomide 75 mg/m2 orally once daily starting the evening before the first RT session over a period of 42 calendar days, with a maximum of 49 days.

Following the RT period, all subjects will receive 28-day oral temozolomide (150 mg/m2 first cycle and 200 mg/m2 all subsequent cycles, as tolerated), administered each weekday.

Company mulls out-licensing for second GBM asset

The study will compare overall survival (OS) at two years. The first patient is expected to be enrolled in January, with enrollment projected to complete by early 2019. Interim safety and efficacy data are possible in 2020, according to the company, with trial completion expected in 2021.

A baseline assessment to determine progression-free survival and overall response rate and to rule out pseudo-progression will occur at 10 weeks via MRI using the modified Response Assessment in Neuro-Oncology, or mRANO, scale. A hazard ratio of 0.67 for the trial corresponds to 22 percent two-year survival in the TSC arm – the lower limit of the 95 percent confidence interval for the biopsy-only subjects in Diffusion's phase II trial – and 10 percent survival in the SOC arm. The estimated median survival is 10 months for the SOC arm vs. 14.9 months for the TSC plus SOC arm.

Diffusion expects the study to achieve the designed 80 percent statistical power at 198 events, defined as death. The first analysis will occur at the earlier of two years of follow-up for all subjects or 198 events.

David Kalergis, co-founder and CEO of Diffusion, declined additional comment on the trial design, citing a quiet period in relation to the company's filing of an S-1 with the SEC last week for an underwritten public offering of up to $14.95 million to fund R&D, including clinical trials, for TSC.

H.C. Wainwright & Co. is sole bookrunner for the offering, which was not priced.

In addition to GBM, the company is exploring TSC for the potential IV treatment of pancreatic cancer and brain metastases. TSC also may have potential benefits for the treatment of hemorrhagic shock, cardiovascular diseases and neurodegenerative diseases, according to Cortellis Competitive Intelligence. A stroke program is under discussion with doctors from the University of California-Los Angeles and the University of Virginia, with whom Diffusion has a joint research program to test TSC in the treatment of stroke, according to the S-1 filing.

The asset has orphan drug designation in the GBM and brain metastases indications.

Diffusion is exploring alternatives, including out-licensing, to advance RES-529, a PI3K/Akt/mTOR inhibitor that completed phase I trials in an intravitreal formulation in age-related macular degeneration and is in preclinical development in oncology, particularly GBM. RES-529, which the company also is studying in oral, inhaled and topical formulations, demonstrated the ability to cross the blood-brain barrier and showed activity in both in vitro and in vivo glioblastoma animal models. The asset also received orphan drug designation from the FDA in GBM.

John Gainer, Diffusion's co-founder and chief scientific officer, invented the trans bipolar carotenoid family of molecules while serving for four decades as a member of the faculty at the University of Virginia, where he was named professor of chemical engineering. His recent research, funded by the Office of Naval Research, focused on the use of these molecules to treat hemorrhagic shock, a major cause of death in combat, and to treat acute respiratory distress syndrome.

Formed in 2004, Diffusion completed a reverse merger in 2015 through an all-stock transaction with a subsidiary of Restorgenex Corp., of Buffalo Grove, Ill., with Diffusion as the surviving entity. Last year, the company's board approved a 1-for-10 reverse split of its outstanding common shares, followed by an up-listing to the Nasdaq Capital Market under the ticker DFFN. On Wednesday, Diffusion's shares closed at $1.21 for a gain of 10 cents.

In its S-1, Diffusion reported cash and equivalents of $11.2 million, an accumulated deficit of $63.3 million and 14.5 million common shares outstanding as of Sept. 30.