Ad-RTS-hIL-12 / Alaunos Therap, Precigen - LARVOL DELTA

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

[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

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

Evaluation of Ad-RTS-hIL-12 + Veledimex in Subjects With Recurrent or Progressive Glioblastoma, a Substudy to ATI001-102 (clinicaltrials.gov) - P1; N=36; Completed; Sponsor: Ziopharm; Active, not recruiting ➔ Completed; Trial completion date: Jun 2021 ➔ Jan 2021

Trial completion • Trial completion date • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • CD4 • CD8 • IFNG • MRI

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; Active, not recruiting; Sponsor: Ziopharm; Trial primary completion date: Dec 2020 ➔ Jun 2021

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

A Study of Ad-RTS-hIL-12 With Veledimex in Subjects With Breast Cancer (clinicaltrials.gov) - P1/2; N=40; Completed; Sponsor: Ziopharm; Active, not recruiting ➔ Completed

Trial completion • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor

Ziopharm Oncology Presents Encouraging Clinical Data for Controlled IL-12 for the Treatment of Glioblastoma and DIPG at the 2020 Society for Neuro-Oncology Annual Meeting (Ziopharm Press Release) - "Ziopharm...today announced the presentation of new clinical data from three ongoing trials of Ad-RTS-hIL-12 plus veledimex (Controlled IL-12) for the treatment of recurrent glioblastoma (rGBM) and diffuse intrinsic pontine glioma (DIPG)...Data highlights include the first discussion of interim data from the phase 2 study of Controlled IL-12 in combination with cemiplimab for the treatment of rGBM...updated interim data from the phase 1 study of Controlled IL-12 in combination with nivolumab for the treatment of rGBM and data from the first patient enrolled in the ongoing phase 1/2 study of Controlled IL-12 monotherapy for the treatment of DIPG...we look forward to future data read-outs in 2021."

P1 data • P1/2 data • P2 data • Glioblastoma • Glioma • Oncology

Ziopharm Oncology Reports Third Quarter 2020 Financial Results and Provides Corporate Update (GlobeNewswire) - "Three abstracts detailing clinical data and observations of Controlled IL-12 have been accepted for presentation at the upcoming 2020 Society for Neuro-Oncology (SNO) virtual annual meeting next month. Updates to be presented on Controlled IL-12 in DIPG (NCT03330197) and combination studies of Controlled IL-12 with Opdivo as a phase 1 trial (NCT03636477) and with Libtayo as a phase 2 trial (NCT04006119) in recurrent glioblastoma (rGBM)."

P1 data • P1/2 data • P2 data • Brain Cancer • Glioblastoma • Oncology

Ziopharm Oncology Granted Rare Pediatric Disease Designation for Controlled IL-12 for the Treatment of DIPG (GlobeNewswire) - “Ziopharm Oncology, Inc…announced that the U.S. Food and Drug Administration (FDA) has granted Rare Pediatric Disease Designation to Ad-RTS-hIL-12 with veledimex (Controlled IL-12) for the investigational treatment of diffuse intrinsic pontine glioma (DIPG), a lethal brain tumor occurring in the pontine region of the brain. DIPG accounts for approximately 10 to 15 percent of all cases of brain tumors in children. The Rare Pediatric Disease Designation program is intended to encourage the development of new drugs and biologics for the prevention and treatment of rare pediatric diseases.”

FDA event • Brain Cancer • Glioma • Oncology

Ziopharm Oncology Completes Enrollment of Phase 2 Trial Evaluating Controlled IL-12 in Combination with Libtayo in Patients with Glioblastoma (Ziopharm Press Release) - "Ziopharm Oncology...announced that 36 subjects have been enrolled in the phase 2 clinical trial evaluating Ad-RTS-hIL-12 with veledimex (Controlled IL-12) in combination with the PD-1 inhibitor Libtayo® (cemiplimab-rwlc) for the treatment of recurrent or progressive glioblastoma (rGBM) in adults. Subjects in this multi-center trial were enrolled from seven hospitals specializing in the treatment of brain cancers across the United States."

Enrollment closed • Glioblastoma • Oncology

Study of Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab in Subjects With Recurrent or Progressive Glioblastoma (clinicaltrials.gov) - P2; N=36; Active, not recruiting; Sponsor: Ziopharm; Recruiting ➔ Active, not recruiting

Clinical • Combination therapy • Enrollment closed • Brain Cancer • Glioblastoma • Oncology • Solid Tumor