Clinical Trials

Date: 2018-06-04

Type of information: Presentation of results at a congress

phase: 1

Announcement: presentation of results at the American Society of Clinical Oncology (ASCO) annual meeting, in Chicago

Company: Ziopharm Oncology (USA - MA)

Product: Ad-RTS-hIL-12 + veledimex - adenoviral vector-RheoSwitch Therapeutic System-human interleukin 12 + veledimex

Action mechanism:

• gene therapy. Ad-RTS-hIL-12 plus veledimex is a novel gene therapy candidate designed to express human interleukin-12 (hIL-12) under the control of an orally administered activator ligand, veledimex, through a proprietary RheoSwitch Therapeutic System® (RTS®) gene switch.
• An ongoing Phase 1 trial is evaluating Ad-RTS-hIL-12 plus veledimex as a monotherapy to treat patients with rGBM, and a separate trial has been initiated to evaluate a single dose of Ad-RTS-hIL-12 plus veledimex in combination with Opdivo® (nivolumab). Ziopharm also is exploring combination therapies with Controlled IL-12 and checkpoint inhibitors in additional tumor types.

Disease: patients with recurrent or progressive glioblastoma or Grade III malignant glioma

Therapeutic area: Cancer - Oncology - Rare diseases

Country: USA

Trial details:

• This research study involves two investigational drugs, veledimex, an activator ligand (INXN-1001) in combination with an Adenovirus Vector Engineered to Express interleukine-12 (INXN-2001). IL-12 is a protein that may improve the body's natural response to disease by enhancing the ability of the immune system to kill tumor cells and may interfere with blood flow to the tumor. The primary objective of the study is to determine the safety and tolerability of a single intra-tumoral Ad-RTS-hIL-12 injection activated upon dosing with oral veledimex. Secondary objectives are to determine the Ad-RTS-hIL-12 + veledimex maximum tolerated dose, the immune responses elicited by Ad-RTS-hIL-12 + veledimex, and assessment of biologic response.
• (NCT02026271)

Latest news:

• • On June 4, 2018, Ziopharm Oncology presented clinical data showing the company’s Controlled IL-12 platform as monotherapy achieved anti-tumor responses in patients with recurrent glioblastoma (rGBM) at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago. The poster, “Demonstration of Anti-Tumor Immunity via Intratumoral Regulated Platform Ad-RTS-hIL-12 in Advanced Breast Cancer and Recurrent Glioblastoma Patients,” presented data from two open-label trials that evaluated Ad-RTS-hIL-12 plus veledimex. Updated data from the Company’s Phase 1 rGBM study shows median overall survival (mOS) of 12.7 months has been sustained for patients treated with Ad-RTS-hIL-12 plus 20mg of veledimex (n=15) at a mean follow-up time of 12.9 months as of May 4, 2018. This mOS of 12.7 months continues to compare favorably to the 5 to 8 months survival established in historical controls for patients with rGBM. In both rGBM and mBC trials, an adenovirus vector with coding for the RheoSwitch Therapeutic System® (RTS®) genetic switch and IL-12 was injected intratumorally and patients took oral doses of veledimex, an activator ligand which controls IL-12 production at the tumor site. The protocol for rGBM trial allowed for patients to receive doses of veledimex between 10 and 40 mg daily over 14 days while patients with mBC received 80mg of veledimex daily for seven days.
• In both tumor types, biopsy data showed consistent, dose-dependent production of IL-12 and interferon gamma and an influx of CD3+ CD8+ cytotoxic T cells. Additionally, there was evidence of sustained intratumoral increase in interferon gamma with undetectable levels of cytokines in systemic circulation in both studies. In the rGBM study, immunofluorescence studies show an overexpression of PD-1/PD-L1 markers. In the mBC study, disease control rate was 44 percent at week 6 and 22 percent at week 12. Reductions in the diameter of both injected and non-injected lesions was observed and considered evidence of an abscopal effect. Overall, Ad-RTS-hIL-12 plus veledimex revealed a consistent and attractive safety profile. In both studies, low grade dose-related transient cytokine release syndrome was the most commonly observed adverse reaction. Drug related toxicities were predictable, dose-related, and fully reversible upon discontinuation of veledimex.
• •On July 19, 2016, Ziopharm Oncology provided an update regarding theongoing multicenter Phase I study of Ad-RTS-hIL-12 + orally administered veledimex in recurrent or progressive glioblastoma (GBM) or grade III malignant glioma. The patient death resulting from intracranial hemorrhage in the third cohort of this Phase I study was deemed unrelated to study drug following the receipt and analysis of additional information by the sponsor and the study's Safety Review Committee. As with all study events, the Company expects to report the data to the FDA in accordance with the study's protocol and applicable regulations. As previously announced, the study remains open for enrollment. The Company expects to provide further updates on the progress of the study, including longer-term survival follow up, at an appropriate meeting later this year.
• • On July 15, 2016, Ziopharm Oncology issued the following statement regarding the Company's ongoing multicenter Phase 1 study of Ad-RTS-hIL-12 + orally administered veledimex in recurrent or progressive glioblastoma (GBM) or grade III malignant glioma: "This Phase I study is being conducted in late-stage, recurrent GBM, so these patients are all, unfortunately, medically fragile.  The first two patient deaths, which occurred 6.7 months and 3.9 months after treatment, were unrelated to study drug. A third death has just been reported to us and we are collecting and analyzing information in order to properly and timely report it to the FDA. The cause of death is intracranial hemorrhage, which occurred some time after the patient had been discharged from the treating center. This is an isolated case, and there have been no reported related instances of brain hemorrhage in any pervious cohort or prior studies with Ad-RTS-hIL-12 + veledimex.  Enrollment remains open in the study, and we will be discussing with our Safety Review Committee the appropriate course of action.  For patients who have experienced multiple recurrences, as these patients have, prognoses are particularly poor. Median follow up in the first dose cohort from our study is now 8 months, in a population with an expected overall survival of 3 to 5 months for patients that have failed temozolomide and bevacizumab, or equivalent salvage chemotherapy.  For the patients that remain in follow up in this Phase I study, we believe that preliminary overall survival remains encouraging.  The Company expects to provide an update once a course of action has been determined."
• • On June 27, 2016, Ziopharm Oncology announced the successful completion of enrollment in the first and second dosing cohorts as well as the initiation of enrollment in a third cohort in the Company's ongoing multi-center Phase 1 study of Ad-RTS-hIL-12 + orally administered veledimex to treat recurrent or progressive glioblastoma (GBM) or grade III malignant glioma.  The primary objective of the study is to determine the safety and tolerability of a single intratumoral Ad-RTS-hIL-12 injection activated upon dosing with oral veledimex. Secondary objectives are to determine the maximum tolerated dose, the immune responses elicited, and assessment of biologic response. The first cohort of seven patients received 20 mg doses of veledimex, the second cohort of six patients received 40 mg doses of veledimex, and the third cohort will receive 30 mg doses of veledimex to refine the effect of activating the immune response within the tumor. The resultant immunologic activity that follows IL-12 expression in the brain suggests that no further dose escalation will be necessary and the optimal dosing may be reached sooner than initially anticipated.
• Data from 11 patients with recurrent high-grade gliomas were recently presented at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting. All of these patients failed at least two prior lines of therapy and underwent partial resection leaving residual tumors, in certain cases with significant tumor burden. Ad-RTS-hIL-12 was administered through direct injection into the brain tumor and veledimex was taken orally to activate the production of IL-12 from the tumor site and stimulate an immune response.
• As of May 18th, the date of data collection for the ASCO presentation, overall median follow up was 6.2 months, with 10 of 11 recipients alive. IL-12 in the bloodstream was measured and was found to be proportional to the amount of veledimex administered, demonstrating that this orally-delivered activator crossed the blood brain barrier to turn on the RheoSwitch® technology in a dose-dependent manner.
• To date, toxicities in both dose cohorts were consistent with those previously reported, with a higher incidence of grade 3 or greater adverse events in the 40 mg dose group. All related side effects were reversed upon cessation of veledimex. No subsequent deaths have been reported.
• • On May 18, 2016, Ziopharm Oncology announced that interim results from the Company's ongoing Phase 1, multi-center dose-escalation study of the gene therapy candidate Ad-RTS-hIL-12 + orally-administered veledimex in patients with recurrent or progressive glioblastoma will be presented at the American Society of Clinical Oncology (ASCO) Annual Meeting held June 3-7, 2016, at McCormick Place in Chicago, Illinois. Ad-RTS-hIL-12 + veledimex is a novel viral gene therapy candidate for the controlled expression of interleukin 12 (IL-12), a pro-inflammatory cytokine critical for stimulating anti-cancer immune responses. Eleven patients with recurrent high-grade gliomas (one with grade III and ten with grade IV) have been treated to date with Ad-RTS-hIL-12 through direct injection into their brain tumors, including seven patients in the first dose cohort (veledimex dosed at 20 mg) and four in the ongoing second dose cohort (veledimex dosed at 40 mg). Veledimex was taken orally to activate the production of IL-12 from the tumor site and stimulate an immune response. Patients enrolled in this multi-center study have all failed standard therapy, with nine of eleven patients failing additional salvage treatments, for a mean of 2.7 prior lines of therapy in cohort one and 2.0 prior lines in cohort two. No enrollment restrictions were placed on tumor size or location within the supratentorial space. Overall median follow-up for patients enrolled in the trial is 6.2 months with 10 of 11 alive. In the fully-enrolled cohort one, 6 of 7 (86%) patients remain alive with a median follow up of 6.8 months. Enrollment in cohort two is ongoing. Even at its lowest dose, the presence of IL-12 in the bloodstream could be detected, demonstrating that veledimex is bioavailable and crosses the blood brain barrier at sufficient levels to turn on the RheoSwitch (RTS^®) and generate IL-12, which could be measured in the blood stream. Furthermore, for those patients that experienced adverse events associated with the treatment, discontinuing veledimex reversed these adverse events. Overall Ad-RTS-hIL-12 + veledimex was well tolerated. All serious adverse events and Grade 3 related toxicities were rapidly reversible upon discontinuation of veledimex. The most common related adverse events included headache, nausea/vomiting, fever, white blood cell/leukocyte count decrease, platelet count decrease and liver function test increase. Four subjects had related serious adverse events.
• • On February 24, 2016, Ziopharm Oncology announced that, following the successful completion of the initial dose cohort, the first patient has been dosed at the succeeding dose level in the Company's ongoing multicenter Phase 1 study of Ad-RTS-hIL-12 + orally administered veledimex in recurrent or progressive glioblastoma or grade III malignant glioma. "This Phase 1 study of Ad-RTS-hIL-12 + veledimex is notable as it is among only a handful of multi-center gene therapy studies ever conducted, involves treatment directly in the brain tumor and addresses an advanced stage of disease where survival outcomes are often dire," said Francois Lebel, M.D., Executive Vice President, Research and Development, Chief Medical Officer at Ziopharm.
• At the Society for Neuro-Oncology 20th Annual Scientific Meeting in November 2015, and in subsequent presentations, the Company announced results, including encouraging activity and "on-target toxicity," as well as evidence that veledimex crosses the blood brain barrier, from the first cohort in the study at a dosing regimen of Ad-RTS-hIL-12 2.0x10^11 + veledimex 20mg/day. After a review of tolerability data from this cohort of seven patients by a panel of independent neuro oncology experts, convened as the Data Safety Monitoring Board for the trial, the next dosing cohort of veledimex (40mg/day) was approved.
• • On November 19, 2015, Ziopharm Oncology announced that the company is presenting initial results from an ongoing Phase 1 dose-escalation study of Ad-RTS-hIL-12 + orally administered veledimex in recurrent or progressive glioblastoma or grade III malignant glioma at the 20th Annual Society for Neuro-Oncology (SNO) Annual Scientific Meeting in San Antonio, Texas (Intratumoral Regulated Expression of IL-12 as a Gene Therapy Approach to Treatment of Glioma). This ongoing trial examines a gene therapy strategy for recurrent high grade gliomas, with the goal of generating a localized anti-tumor immune response. The study is expected to enroll up to 72 subjects. Five patients are now available for initial assessment, two with recurrent grade III malignant glioma and three with grade IV. Results show IL-12 was detectable in peripheral blood along with downstream IFNg, indicating that veledimex crossed the blood brain barrier activating IL-12 expression from intra-tumorally administered Ad-RTS-hIL-12. Ad-RTS-hIL-12 + veledimex was well tolerated with minimal neurologic toxicity. The most common adverse events were headache, fever, hyponatremia and nausea/vomiting. Related serious adverse events were aseptic meningitis, neutropenia, thrombocytopenia, leukopenia, with all toxicity to date consistent with the "on-target" effects of immunotherapy.
• • On May 5, 2015, Ziopharm Oncology announced the initiation of a Phase 1 study of Ad-RTS-hIL-12 + veledimex in patients with recurrent or progressive glioblastoma or Grade III malignant glioma. The Phase 1 study is designed to examine a gene therapy treatment strategy for high grade gliomas with the goal of generating an anti tumor T cell immune response. Eligible patients will be stratified to one of two groups, according to clinical indication for tumor resection. One group will undergo resection plus injection and the other group will undergo stereotactic injection. Ad-RTS-hIL-12 will be injected locally in the tumor lesion, with IL-12 expression levels tightly regulated by escalating doses of the oral activator ligand veledimex. This strategy makes it feasible to control the gene therapy in vivo and to lower or terminate IL-12 expression in the event of severe or unexpected toxicities. The primary objective of the study is to determine the safety and tolerability of a single intra tumoral Ad-RTS-hIL-12 injection plus escalating oral veledimex doses. Secondary Objectives are to determine the veledimex maximum tolerated dose, the immune responses elicited by Ad-RTS-hIL-12 and veledimex, and investigator assessment of response, including the tumor objective response rate and progression-free survival, and determine overall survival, among other measures. The study is expected to enroll up to 72 subjects at up to 12 leading treatment centers. Among the centers expected to begin enrollment are the Stanford School of Medicine, Dana Farber/Brigham and Women's, the University of Chicago Pritzker School of Medicine, Cedars-Sinai/the David Geffen School of Medicine at the University of California, Los Angeles, and Northwestern Memorial Hospital.

Is general: Yes