veledimex (INXN-1001) / University of Pennsylvania - LARVOL DELTA

Adenoviral Vector Monotherapy or Combination With Chemotherapy in Subjects With Recurrent/Metastatic Breast Cancer. (clinicaltrials.gov) - P2 | N=12 | Terminated | Sponsor: 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.

Monotherapy • Trial termination • Breast Cancer • Oncology • Solid Tumor • IL12A • MUC1

A Study of Ad-RTS-hIL-12 With Veledimex in Subjects With Breast Cancer (clinicaltrials.gov) - P1/2 | N=9 | Terminated | Sponsor: 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.

Trial termination • Breast Cancer • Oncology • Solid Tumor

Study of Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab in Subjects With Recurrent or Progressive Glioblastoma (clinicaltrials.gov) - P2 | N=40 | Terminated | Sponsor: Alaunos Therapeutics | Completed ➔ Terminated; Sponsor Decision

Trial termination • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

PD-1 inhibition can be combined with IL-12 in subjects with recurrent glioblastoma (SNO 2019) - P1; "Monotherapy with intratumoral Ad-RTS-hIL-12 (Ad), a novel gene therapeutic conditionally expressing IL-12 under the transcriptional control of oral veledimex (V, 20 mg) acting via the proprietary RheoSwitch Therapeutic System® (RTS®), was shown in a phase 1 Main study (NCT02026271) to elicit a sustained intra-tumoral activated cytotoxic T-cell response with co-expression of PD-1...In the first two cohorts (where data is available), combination therapy improved the biomarker “cytoindex” (ratio of circulating CD8+ T cells to FoxP3+ regulatory T cells)...Controlled IL-12 production using Ad+V with nivolumab is a rational combination with initial data consistent with immune-mediated anti-tumor effects with a favorable safety profile. Further phase 2 investigation of Ad+V plus a checkpoint inhibitor in rGBM is planned."

Clinical • IO Biomarker • PD(L)-1 Biomarker • FOXP3 • IL12A

Survival of subjects with recurrent glioblastoma receiving intra-tumoral administration of IL-12 managed with low-dose dexamethasone (SNO 2019) - P1; "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."

Clinical • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • FOXP3 • IFNG • IL12A

Evaluation of controlled IL-12 in combination with a PD-1 inhibitor in subjects with recurrent glioblastoma. (ASCO 2019) - P1; "Background: Ad-RTS-hIL-12 (Ad) is a novel gene therapy candidate conditionally expressing IL-12 under the control of veledimex (V) acting via the proprietary RheoSwitch Therapeutic System (RTS) gene switch with a therapeutic window. Controlled IL-12 production using Ad + V with nivo is a rational combination with initial data consistent with immune-mediated anti-tumor effects with a favorable safety profile, warranting continued investigation in rGBM. Clinical trial information: NCT03636477"

Clinical • Combination therapy • IO Biomarker • PD(L)-1 Biomarker

Expanded phase I study of intratumoral Ad-RTS-hIL-12 plus oral veledimex: Tolerability and survival in recurrent glioblastoma. (ASCO 2017) - P1; "OS in patients who have failed temozolomide, bevacizumab or equivalent salvage chemotherapy, is ~3-5 months. Overall, Ad + 20 mg V is well tolerated; toxicities were predictable and reversible upon discontinuing V. There is a correlation between V dose, BBB penetration and drug related AEs. The tolerability and encouraging survival observed to date warrant further investigation in a pivotal trial. A stereotactic arm and a pediatric trial in diffuse intrinsic pontine glioma patients are planned."

Clinical • P1 data • Biosimilar • Oncology

[VIRTUAL] Combination of Controlled Interleukin-12 Gene Therapy with Immune Checkpoint Blockade in Recurrent Glioblastoma: Updated Results of a Multi-Institutional, Open Label Phase 1 Trial (SNO 2020) - P1 | "A published clinical trial of veledimex (V)-regulatable interleukin-12 (IL-12) gene therapy (“Controlled IL-12”) under the control of a transcriptional switch (RheoSwitch Therapeutic Systemâ, RTSâ) as monotherapy in recurrent glioblastoma (rGBM) showed sustained infiltration of activated T cells within the tumor months after treatment (Sci Transl Med...These T cells demonstrated up-regulation of immune checkpoint signaling, providing a rationale for combination therapy with the PD-1 inhibitor, nivolumab (nivo)...Baseline and post-treatment histochemical staining and multiplex immunofluorescence analyses for a subgroup of subjects will be discussed. The safety of this combination immunotherapy has been established, leading to a currently accruing phase 2 clinical trial of loco-regional Controlled IL-12 gene therapy in combination with the PD-1 inhibitor cemiplimab-rwlc (NCT 04006119)."

Checkpoint inhibition • Clinical • P1 data • Gene Therapies • Glioblastoma • Immune Modulation • Inflammation • Oncology • Solid Tumor • IL12A

[VIRTUAL] Phase 2 Trial of Controlled IL-12 in Combination with PD-1 Inhibitor in Adult Subjects with Recurrent Glioblastoma (rGBM) (SNO 2020) - P2 | "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."

Clinical • Combination therapy • IO biomarker • P2 data • Gene Therapies • Glioblastoma • Oncology • Solid Tumor • IFNG • IL12A • MRI

A Study of FCX-013 Plus Veledimex for the Treatment of Moderate to Severe Localized Scleroderma (Morphea) (clinicaltrials.gov) - P1/2 | N=1 | Terminated | Sponsor: Castle Creek Biosciences, LLC. | N=10 ➔ 1 | Trial completion date: Jan 2036 ➔ Apr 2022 | Recruiting ➔ Terminated; Sponsor decision

Enrollment change • Trial completion date • Trial termination • Fibrosis • Immunology • Scleroderma • Systemic Sclerosis

Disheveling Tumor’s Intrinsic Immunosuppression to Improve IL-12 Therapy in Glioblastoma (ASGCT 2022) - "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."

IO biomarker • Brain Cancer • Gene Therapies • Glioblastoma • Glioma • Oncology • Solid Tumor • CD8 • IFNG • IL12A

A Study of FCX-013 Plus Veledimex for the Treatment of Moderate to Severe Localized Scleroderma (Morphea) (clinicaltrials.gov) - P1/2 | N=10 | Recruiting | Sponsor: Castle Creek Biosciences, LLC. | Trial primary completion date: Mar 2022 ➔ Jun 2022

Trial primary completion date • Fibrosis • Immunology • Scleroderma • Systemic Sclerosis

Combined immunotherapy with controlled Interleukin-12 gene therapy and immune checkpoint blockade in recurrent glioblastoma: an open-label, multi-institutional phase 1 trial. (PubMed, Neuro Oncol) - P1, P2 | "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)."

Checkpoint inhibition • Clinical • Journal • P1 data • Brain Cancer • Gene Therapies • Glioblastoma • Immune Modulation • Inflammation • Oncology • Solid Tumor • CD8 • IFNG • IL12A

Final Results of Controlled IL-12 Monotherapy and in Combination with PD-1 inhibitor in Adult Subjects with Recurrent Glioblastoma (SNO 2021) - P1, P2 | "Ad-RTS-hIL-12(Ad) is a gene therapy candidate conditionally expressing IL-12 under the transcriptional control of veledimex(V) acting via the RheoSwitch Therapeutic System® gene switch...Ziopharm has conducted 3 phase-I (NCT02026271/NCT03679754 (monotherapy), NCT03636477 (combination with nivolumab)) and one phase-ll (NCT04006119) multicenter, open-label, single-arm trial in subjects with rGBM is evaluating Ad (single intratumoral injection, 2 x 10 11 -viral-particles, Day0) with oral V dosing (20mg, Days 0-14) with cemiplimab infusions (350 mg IV) on Days -7, 15, then Q3W...Final survival data and results from neoepitope analysis will be presented. Further investigation is warranted to understand the impact of monotherapy vs. combination, concurrent steroids use and unifocal vs. multifocal disease on overall survival in subjects with rGBM receiving Controlled-IL-12."

Clinical • Combination therapy • IO biomarker • Monotherapy • Brain Cancer • Gene Therapies • Glioblastoma • Oncology • Solid Tumor • IL12A

Study of Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab in Subjects With Recurrent or Progressive Glioblastoma (clinicaltrials.gov) - P2; N=40; Completed; Sponsor: Ziopharm; Active, not recruiting ➔ Completed; Trial completion date: Aug 2022 ➔ Aug 2021; Trial primary completion date: Jun 2022 ➔ Aug 2021

Clinical • Combination therapy • Trial completion • Trial completion date • Trial primary completion date • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • MRI

A Study of Ad-RTS-hIL-12 + Veledimex in Pediatric Subjects With Brain Tumors Including DIPG (clinicaltrials.gov) - P1/2; N=6; Terminated; Sponsor: 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

Clinical • Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Brain Cancer • Diffuse Intrinsic Pontine Glioma • Glioma • Oncology • Pediatrics • Solid Tumor • CTLA4 • IFNG • MRI

A Study of Ad-RTS-hIL-12 With Veledimex in Subjects With Breast Cancer (clinicaltrials.gov) - P1/2; N=9; Completed; Sponsor: Ziopharm; N=40 ➔ 9

Clinical • Enrollment change • IO biomarker • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor

[VIRTUAL] Controlled IL-12 in combination with a PD-1 inhibitor subjects with recurrent glioblastoma. (ASCO 2020) - P1 | "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"

Clinical • Combination therapy • IO biomarker • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • CD8 • IFNG • IL12A

A Study of Ad-RTS-hIL-12 With Veledimex in Combination With Nivolumab in Subjects With Glioblastoma; a Substudy to ATI001-102 (clinicaltrials.gov) - P1; N=21; Completed; Sponsor: Ziopharm; Active, not recruiting ➔ Completed; Trial completion date: Dec 2021 ➔ Jun 2021; Trial primary completion date: Jun 2021 ➔ Oct 2020

Clinical • Combination therapy • Trial completion • Trial completion date • Trial primary completion date • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • MRI

Demonstration of anti-tumor immunity via intratumoral regulated platform ad-RTS-hIL-12 in advanced breast cancer and recurrent glioblastoma patients. (ASCO 2018) - P1,P1/2; "NCT02026271; NCT02423902 Background: Ad-RTS-hIL-12 (Ad) is a novel gene therapy candidate expressing IL-12 under the control of an orally administered activator ligand, veledimex (V), through a proprietary RheoSwitch Therapeutic System (RTS) gene switch. Local regulated controlled IL-12 expression using the Ad + V platform in advanced mBC and rGBM patients is promising, eliciting sustained increases in cytotoxic T cells, reduces Treg, including in non-injected lesions (abscopal effect) turning cold tumors hot, with a good safety profile. This platform warrants further evaluation in multiple tumor types in monotherapy and in combination with immune checkpoint inhibitors."

Clinical • IO biomarker • Hormone Receptor Breast Cancer

Evaluation of controlled IL-12 as monotherapy in subjects with recurrent GBM. (ASCO 2019) - P1; "It was conditionally produced in Ph1 “main” study (NCT02026271) in subjects with recurrent glioblastoma (rGBM) using a replication-incompetent adenovirus modified to express IL-12 under transcriptional control of the proprietary RheoSwitch Therapeutic System (Ad-RTS-hIL-12, Ad) regulated by dose of veledimex (V). Local, controlled IL-12 production using the Ad + V platform in subjects with rGBM safely activates the immune system and when dex is limited, appears to further improve mOS, which warrants continued investigation. Clinical trial information: NCT03679754"

Clinical • IO Biomarker • Monotherapy

[VIRTUAL] Survival of subjects with recurrent glioblastoma receiving intratumoral administration of controlled IL-12 with limited exposure to dexamethasone. (ASCO 2020) - P1 | "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..."

Clinical • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • IFNG • IL12A

[VIRTUAL] Final results of controlled IL-12 monotherapy in adults with grade III or IV gliomas. (ASCO 2020) - P1 | "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."

Clinical • Monotherapy • Brain Cancer • Immune Modulation • Inflammation • Oncology • Solid Tumor • IFNG • IL12A

Evaluation of controlled IL-12 in combination with a PD-1 inhibitor in subjects with recurrent glioblastoma. (ASCO 2019) - P1; "Background: Ad-RTS-hIL-12 (Ad) is a novel gene therapy candidate conditionally expressing IL-12 under the control of veledimex (V) acting via the proprietary RheoSwitch Therapeutic System (RTS) gene switch with a therapeutic window. Controlled IL-12 production using Ad + V with nivo is a rational combination with initial data consistent with immune-mediated anti-tumor effects with a favorable safety profile, warranting continued investigation in rGBM. Clinical trial information: NCT03636477"

Clinical • Combination therapy • IO Biomarker • PD(L)-1 Biomarker

A Study of Ad-RTS-hIL-12 With Veledimex in Subjects With Glioblastoma or Malignant Glioma (clinicaltrials.gov) - P1; N=40; Completed; Sponsor: Ziopharm; Active, not recruiting ➔ Completed

Trial completion • Anaplastic Oligoastrocytoma • Astrocytoma • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • MRI