On November 23, 2019 Ziopharm Oncology, Inc. ("Ziopharm" or the "Company") (Nasdaq:ZIOP), reported the presentation of new interim analyses of clinical data from two ongoing substudies in its Controlled IL-12 platform, or Ad-RTS-hIL-12 plus veledimex (Ad+V), both as monotherapy and in combination with a PD-1 inhibitor, for the treatment of recurrent or progressive glioblastoma multiforme (rGBM) in adults, at the 2019 Society for Neuro-Oncology (SNO) Annual Meeting in Phoenix (Press release, Ziopharm, NOV 23, 2019, View Source [SID1234551642]).

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"Recurrent GBM is a complex disease which grows by walling itself off from the immune system, making it so devastating. It appears that placing IL-12 within the tumor and then controlling the production of this cytokine, drives T cells into the tumor, enabling the immune system to adapt, which leads to anti-tumor activity," said Laurence Cooper, M.D., Ph.D., CEO of Ziopharm. "We are encouraged by the findings presented at SNO, as we advance the clinical development of Controlled IL-12 as a monotherapy and in combination with immune checkpoint inhibitors, including a phase 2 study which is currently enrolling."

The Company announced in February 2019 the completion of the enrollment in an "Expansion" substudy (Clinicaltrials.gov NCT03679754) that enlarged the phase 1 "Main" trial (Clinicaltrials.gov NCT02026271) by an additional 36 patients with rGBM receiving Ad-RTS-hIL-12 plus 20mg/day veledimex for up to 14 days. Results from this substudy were presented yesterday (7:30 pm MST) in a poster presentation titled "Survival of Subjects with Recurrent Glioblastoma Receiving Intra-tumoral Administration of IL-12 Managed with Low-dose Dexamethasone":

Interim Update Reported

Decrease in tumor from baseline (time of Ad+V administration) resulting in a patient’s lesion being too small to measure, assessed as a partial response (per iRANO), with follow up ongoing

Subjects were comparable to the Main study except a higher percentage in the Expansion substudy had multifocal disease vs. unifocal disease and fewer recurrences

Based on study design there was, as expected, a higher percentage of subjects in the Expansion substudy as compared with Main study (75% vs 40%) who received low-dose concurrent steroids

Local, regulated IL-12 production using Ad+V in subjects with rGBM rapidly and safely activates the immune system

Peak serum IL-12 at Day 3 with downstream production of endogenous IFN-g peaking at Day 7 in Expansion substudy (and Main study)

MRI findings of pseudoprogression, consistent with immune-mediated anti-tumor effects

20mg V subjects (Main + Expansion, n=20) with unifocal disease at entry, receiving low-dose steroids (defined as <20 mg cumulative dosing of dexamethasone) continued to show a trend towards longer median overall survival (mOS, 16.2 months)

Adverse reactions (ARs) were consistent with prior studies of Ad+V, predictable, dose-related, and promptly reversible upon discontinuation of veledimex

No drug-related deaths were reported

In the Main study, six subjects with unifocal disease at entry, receiving low-dose steroids (defined as <20 mg cumulative dosing of dexamethasone) were previously reported to have mOS of 17.8 months. The mOS for these patients in the Expansion substudy (n=14) has not been reached at a mean follow up of 9.7 months.

Literature shows that multifocal GBM is associated with worse prognosis compared to unifocal disease. 1,2 The data from the Main study and the Expansion substudy are consistent with this prognosis, with mOS of 10.1 months for patients (n=13) with multifocal disease at entry that received 20mg veledimex and low-dose steroids.

The Company previously reported on serial biopsies in patients with rGBM which demonstrated Controlled IL-12 resulted in sustained influx of T cells with upregulation of PD-1 expression. This supports combining Ad-RTS-hIL-12 plus veledimex for up to 14 days with the PD-1 inhibitor nivolumab (Clinicaltrials.gov NCT03636477). The Company announced completion of dose escalation in June 2019 and recently reported enrollment of an additional 12 patients at the highest dosing level. Data and observations presented today (5 pm MST) in a poster presentation titled "PD-1 Inhibition can be Combined with IL-12 in Subjects with Recurrent Glioblastoma":

Interim Update Reported

Decrease by 64% in a patient’s tumor from baseline (time of Ad+V administration) resulting in a partial response (per iRANO) with follow up ongoing

Enrollment is complete per 3+3 (Ad+V and nivolumab) dose-escalation, as well as an additional 12 patients enrolled to the third cohort (highest dose)

Cancer Manag Res. 2018;10:4229–4235

Int. J. Mol. Sci. 2017, 18, 2469

Mean follow up is 4.8 months (with a minimum of 0.9 months and a maximum of 16.9 months); active dosing is ongoing, and mOS has not been reached

Serum IL-12 was detected in all subjects following initiation of Ad+V, which is consistent with previously reported data on Ad+V as monotherapy

MRI findings of pseudoprogression, consistent with immune-mediated impact on tumor

No dose limiting toxicities, no serious adverse events that were considered related to the combination with nivolumab and no clinically significant overlapping toxicities were observed

Drug-related toxicities in the combination substudy were comparable to the Main study, being predictable, dose-related, and promptly reversible upon discontinuation of veledimex and with no drug related deaths

"The two phase 1 trials evaluating Controlled IL-12 yield encouraging clinical data. We now have the experience to dose Ad-RTS-hIL-12 + veledimex as monotherapy and in combination with immune checkpoint inhibitors in patients with recurrent glioblastoma. While it is early days, the approach appears to be working as we can regulate IL-12 using a switch, we see evidence of pseudoprogression followed by anti-tumor effects, and there is encouraging survival in some patients with rGBM which is typically rapidly fatal," said Dr. Antonio Chiocca, M.D., Ph.D., poster author and Professor of Neurosurgery at Harvard Medical School, Surgical Director of the Center for Neuro-Oncology at Dana-Farber Cancer Institute, and Chairman of Neurosurgery and Co-Director of the Institute for the Neurosciences at Brigham and Women’s Hospital.

"Recurrent glioblastoma is a devastating brain cancer with few treatment options demonstrating success and a significant need for new treatment options. The Controlled IL-12 platform, that appears to have activity as monotherapy, supports combining Controlled IL-12 with a PD-1 inhibitor. This combination builds on a solid scientific rationale and has yielded data of relevant immune activity that supports continued development," Rimas Lukas, M.D., poster author and Associate Professor of Neurology (Neuro-Oncology), Northwestern University Feinberg School of Medicine and Department of Neurology, University of Chicago.

These data support Ziopharm’s continued development of its Ad-RTS-hIL-12 plus veledimex as a drug to control the production of IL-12 as monotherapy and in combination with PD-1 inhibition. The Company commenced a phase 2 trial to evaluate Controlled IL-12 in combination with Regeneron Pharmaceuticals’ PD-1 antibody Libtayo (cemiplimab-rwlc) in June 2019.

Learn more about Controlled IL-12 online at View Source The posters presented at the SNO 2019 Annual Meeting will be available on the Company’s website in the "Scientific and Medical Publications" section.