Ziopharm Reports Initial Positive Data Presented at 2011 Asco, Zin-cti-001 Well Tolerated

ZIOPHARM Oncology, Inc. ZIOP announced today that Douglas J. Schwartzentruber, MD, FACS, of the Indiana University Health Goshen Center for Cancer Care, presented initial positive clinical results from the first-ever treatment demonstrating control over transgene encoding of a therapeutic anticancer protein in humans using a small molecule activator ligand. These results were presented at the 2011 Annual Meeting of the American Society of Clinical Oncology being held June 3 – 7, in Chicago, IL. The Phase Ib study of DC-RTS-IL-12, also referred to as ZIN-CTI-001, in patients with advanced melanoma, entitled “Immunotherapy of advanced melanoma by intra-tumoral injections of autologous, purified dendritic cells transduced with gene construct of interleukin-12, with dose-dependent expression under the control of an oral activator ligand,” was presented in the Developmental Therapeutics – Clinical Pharmacology and Immunotherapy Poster Session (Poster #1A, Abstract #2540). ZIN-CTI-001, the Company's most advanced synthetic biology product candidate, employs autologous dendritic cells transduced with a controllable gene switch, and a gene for expressing Interleukin-12 (IL-12), a potent anticancer protein. Ten patients with advanced melanoma have been enrolled in the study of a range of doses of an orally administered activator ligand. ZIN-CTI-001 injected intratumorally, then “switched on” by the AL, demonstrated a balance of tolerability (primarily mild to moderate adverse events) and response (a substantial disease control rate of 50% among evaluable patients (n=8)). The data also showed a correlation between T-cell immune responses and clinical outcome, a desired outcome with the highly focused use of IL-12, with limited adverse events and one significant adverse event that completely resolved. “IL-12, an important regulator of immune response to cancer and other diseases, is a protein whose use as a recombinant protein therapy has to date been limited by substantial systemic toxicity,” said Dr. Schwartzentruber, lead author of the study. “By using a small-molecule activator ligand to ‘switch on' an intracellularly delivered gene that produces IL-12 right in the tumor, we have much more control over IL-12's potent antitumor effects. These data, the first in humans to test this novel system, have yielded encouraging results that include disease control predictive of clinical benefit, and warrant further clinical study.” John M. Kirkwood, MD, of the University of Pittsburgh Cancer Institute and co-author of the study, added, “These data demonstrate the clinical application of a new and promising technology, enabling the controlled expression of therapeutic proteins manufactured within the body. This study of intratumoral generation of IL-12 and associated proteins that may augment anti-melanoma T-cell immunity in the tumor will be important to validate in larger studies.” Results in Detail The study enrolled ten patients (median age 61) with unresectable Stage III or IV melanoma. Primary endpoints were safety and tolerability. Secondary endpoints included response, single dose and steady-state pharmacokinetics of the oral AL, an analysis of IL-12 and associated proteins, and cellular immune response (anti-melanoma and immunoregulatory cells) in blood and tissue biopsies. Patients were treated with autologous ZIN-CTI-001 cells (~ 5 x 10⁷) injected into accessible tumors, in combination with AL (escalating between 0.6 – 200 mg daily) administered orally for 14 days per treatment cycle (≤ five (5) treatment cycles). Safety, mechanism of action (genomic and immunologic) and clinical responses were assessed. Among eight evaluable patients, partial or complete regression of injected and some uninjected lesions was observed by CT in three patients, with one patient having RECIST PR of >11 months and three patients demonstrating stable disease by RECIST, for an overall disease control rate of 50%. Further, the results confirmed that intratumoral generation of IL-12 and associated proteins lead to systemic anti-melanoma T cell immunity including cytotoxic CD8+ T cells and TH1 CD4+ cells, without any evidence of increased T regulatory cells or myeloid-derived suppressor cells. Treatment was generally well tolerated, and maximum tolerated dose has not yet been reached. AEs were mild to moderate, with one to two (1-2) patients each experiencing nausea, vomiting, anorexia, arthralgia, fever or chills. One SAE was reported 18 hours after treatment onset with 60 mg AL + ZIN-CTI-001, and included diarrhea, followed by hypotension and reversible acute renal failure, which completely resolved.