veledimex (INXN-1001)

P2, N=12, Terminated, Alaunos Therapeutics | The SRC reduced 140 mg to 100 mg, then to 80 mg. The study ended with one subject enrolled at 80 mg daily.

P1/2, N=9, Terminated, Alaunos Therapeutics | Completed --> Terminated; The study was terminated after 9 subjects had enrolled under Protocol Amend 1 because of slower than expected accrual. Protocol Amendment 2 (16 May 2016) was submitted to the FDA and, based on the decision of the PI, was not submitted to the IRB.

P2, N=40, Terminated, Alaunos Therapeutics | Completed --> Terminated; Sponsor Decision

Phase I clinical trial based on Veledimex (VDX)-regulatable interleukin-12 (IL-12) gene therapy in recurrent high-grade glioma patients showed encouraging results with an overall increase in immune cell infiltration in tumors...INCR1 knockdown could remarkably enhance PBMCs-mediated tumor sphere destruction in the presence of IL-12. In conclusion, targeting INCR1 represents a rational therapeutic strategy to improve IL-12 therapy.

The safety of this combination immunotherapy was established and has led to an ongoing phase 2 clinical trial of immune checkpoint blockade with controlled IL-12 gene therapy (NCT04006119).

P1/2, N=6, Terminated, Ziopharm | N=45 --> 6 | Trial completion date: Dec 2024 --> Sep 2021 | Recruiting --> Terminated | Trial primary completion date: Dec 2022 --> Sep 2021; Sponsor decision due to slow accrual

P1, N=36, Completed, Ziopharm | Active, not recruiting --> Completed | Trial completion date: Jun 2021 --> Jan 2021

An oral activator ligand, veledimex (VDX), controls transcription levels...We describe a patient with a recurrent grade 4 IDH mutant astrocytoma which developed subclones of inactivating DNA mismatch repair (MMR) gene alterations after temozolomide (TMZ) therapy...Post-mortem analysis revealed that DNA MMR alterations were still gone; the previously observed inflammatory infiltrates were also gone. These data suggest that TMZ-driven DNA MMR inactivation is a sub-clonal process, and that MMR-deficient tumor sub-clones are preferentially targeted through immunotherapy.

Ad-RTS-hIL-12 (Ad) is a gene therapy candidate for intratumoral (IT) delivery that conditionally expresses IL-12 (IL-12) under the transcriptional control of orally administered veledimex (V) acting via the RheoSwitch Therapeutic Systemâ gene switch...This phase 2 trial (NCT04006119) in adults with rGBM is evaluating safety and efficacy (overall survival) of Ad + V with pre/post-operative cemiplimab-rwlc (cemi) 350 mg IV, Days -7, 15, then Q3W; Ad single IT injection (2 x 1011 viral particles, day of resection (Day 0) /craniotomy); and V (20 mg PO, Days 0-14)...V crossed the blood-brain barrier to produce functional IL-12. Controlled IL-12 therapy and cemi is a rational combination with initial data consistent with immune-mediated anti-tumor effects with a favorable safety profile.

P1/2, N=45, Recruiting, Ziopharm | Active, not recruiting --> Recruiting | Phase classification: P1 --> P1/2 | N=24 --> 45 | Trial completion date: Mar 2021 --> Dec 2024 | Trial primary completion date: Mar 2021 --> Dec 2022

This phase 1 trial (NCT02026271) is the first to evaluate the safety and tolerability of Ad-RTS-hIL-12 (Ad) under transcriptional control with veledimex (V) in adults with grade III or IV gliomas...Subjects with unifocal disease (n = 6) who received low-dose (≤ 20mg total) dexamethasone during active dosing (Days 0-14) had an mOS of 17.8 mons... Results of Controlled IL-12 in rGBM are promising, with V-dependent and proportional increases in IL-12 and IFN-g resulting in immune activation, with a favorable safety profile and encouraging survival. The 20 mg V dose is the recommended phase 2 dose. Controlled IL-12 is being evaluated in a monotherapy substudy (n = 36, V 20 mg) and two combination studies with immune checkpoint inhibitors for rGBM.

Background: Monotherapy with intratumoral Ad-RTS-hIL-12 (Ad), a gene therapeutic conditionally expressing IL-12 under the transcriptional control of oral veledimex (“Controlled IL-12”), was shown in a phase 1 study (NCT02026271) to elicit a new and sustained intra-tumoral infiltration of T cells with co-expression of PD-1. We report updated findings following completion of enrollment (with follow-up ongoing) for a phase 1 substudy (NCT03636477) evaluating safety and tolerability of local, Controlled IL-12 in combination with nivolumab (nivo) in adults with recurrent glioblastoma (rGBM)... Controlled IL-12 with PD-1 inhibition is a rational combination with initial data consistent with immune-mediated effects, a favorable safety profile, and early evidence of anti-tumor effects. An additional phase 2 study combining Controlled IL-12 with cemiplimab-rwlc in adults with rGBM is ongoing. Research Funding: Ziopharm Oncology