veledimex (INXN-1001)

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.

A phase 1 “main study” (NCT02026271) enrolled subjects with Grade III or IV gliomas who at the time of resection received intratumoral administration of a replication-deficient adenovirus expressing IL-12 under control of a transcriptional switch (Ad-RTS-hIL-12, Ad) regulated by veledimex (V), referred to as “Controlled IL-12”... Multicenter, phase 1 substudy (NCT03679754) that assesses safety and tolerability of Controlled IL-12 by local injection (Day 0, time of resection) of Ad (2 x 1011 viral particles) + V (20 mg PO QD x15 doses, Days 0-14) in subjects that were bevacizumab naïve and not receiving dex 4 weeks prior to Ad... Monotherapy with Controlled IL-12 resulted in sustained increase in serum recombinant IL-12 and downstream endogenous IFN-g. There is evidence of immune-mediated anti-tumor effects which is associated with increased mOS as compared with historical controls. Follow up will investigate the adverse impact of dex, as well as the effect of additional subject characteristics (e.g., unifocal vs.

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

Ad-RTS-hIL-12 (Ad) is a novel gene therapy, conditionally expressing IL-12 via the RheoSwitch Therapeutic System® (RTS®) gene switch under control of an oral activator ligand, veledimex (V)...The mechanism of action of Ad+V is based on controlled secretion of recombinant IL-12 (measured in peripheral blood as a surrogate for intra-tumor-production), downstream upregulation of endogenous IFN-g (measured in peripheral blood), and an increase in the “cytoindex” (ratio of circulating CD8+ T cells to FoxP3+ regulatory T cells), an emerging biomarker of overall survival...As of 04Jun19, mOS in the Expansion substudy had not yet been reached (patient enrollment occurred from September 2018-February 2019). Most subjects (65%) received low-dose dexamethasone (cumulative ≤20mg Days 0-14); initial impact of this and other subject characteristics on survival will be presented.