Date: 2018-06-04
Type of
information: Presentation of results at a congress
phase: 1b-2
Announcement: presentation of results at the European Society for Medical Oncology (ESMO) 2016 Congress
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 + veledimex is a novel gene therapy which controls local expression of IL-12 and may induce tumor stroma collapse and stimulation of an anti-cancer T cell immune response. The ability to regulate the production of IL-12 by modulating veledimex dosing is designed to improve its therapeutic index with standard of care.
Disease: patients with locally advanced or metastatic breast cancer
Therapeutic
area: Cancer - Oncology
Country: USA
Trial
details:
- This single-arm, phase Ib/II study will examine the safety, tolerability and preliminary efficacy of one cycle of Ad-RTS-hIL-12 immunotherapy in women with advanced breast cancer and pre-study SD or PR after completion of a minimum 12 week course of standard first- or second-line chemotherapy. The patient population will include patients with locally advanced or metastatic breast cancer of all subtypes. (NCT02423902)
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 October 10, 2016, Ziopharm Oncology announced the presentation of preliminary data from its Phase 1b/2 study of Ad-RTS-hIL-12 + veledimex following standard chemotherapy for the treatment of patients with locally advanced or metastatic breast cancer. The poster presentation, titled "Phase 1b/2 study of intratumoral Ad-RTS-hIL-12+veledimex in patients with chemotherapy-responsive locally advanced or metastatic breast cancer," was presented at the European Society for Medical Oncology (ESMO) 2016 Congress today in Copenhagen, Denmark. The study, which is being conducted at the Memorial Sloan Kettering Cancer Center in New York, is designed to examine the safety, tolerability and efficacy of Ad-RTS-hIL-12 immunotherapy in up to 40 women with locally advanced or metastatic breast cancer of all subtypes. Following entry into the trial, patients go on a chemotherapy holiday and enter an immunotherapy phase of treatment. A single cycle of Ad-RTS-hIL-12, along with the oral activator ligand veledimex, is given during the immunotherapy phase, with the goal of maintaining or improving pre-study response.
- As of August 30, 2016, a total of nine patients were available for initial assessment. Results show that Ad-RTS-hIL-12 + 7 days of veledimex consistently elicited production of IL-12 which in turn produced IFN?. It was notable that the intratumoral influx of CD8+ T cells and IFN? were present six weeks after completion of veledimex consistent with the ability of Ad-RTS-hIL-12 to favorably impact the tumor environment over the long term. In two patients, Ad-RTS-hIL-12 + veledimex provided a meaningful drug holiday, with durable responses for 18 and 35 weeks. In all patients, disease control rate (DCR) was 44% at Week 6 and 22% at Week 12. Overall response rate (ORR), defined as achieving a partial response (PR) or better, was 11% at Week 12. Most toxicities promptly reversed upon discontinuation of veledimex, including cytokine release syndrome (grade 1-2 CRS), observed in six of nine patients. The higher than expected incidence of CRS was likely related to CYP-3A4 drug interactions with veledimex (80 mg) which resulted in enhanced peak cytokine expression.
- • On December 10, 2015, Ziopharm Oncology announced the presentation of the study design and a trial update for a Phase 1b/2 study of Ad-RTS-hIL-12 + veledimex following standard chemotherapy for the treatment of patients with locally advanced or metastatic breast cancer. The poster presentation titled "Phase 1b/2 study of intratumoral Ad-RTS-hIL-12 + veledimex in patients with chemotherapy-responsive locally advanced or metastatic breast cancer," was presented as part of the "Ongoing Trials - Immunotherapy" session of the 2015 San Antonio Breast Cancer Symposium.
- The study, which is being conducted at the Memorial Sloan Kettering Cancer Center in New York, is designed to examine the safety, tolerability and efficacy of Ad-RTS-hIL-12 immunotherapy in up to 40 women with locally advanced or metastatic breast cancer of all subtypes. Enrollment began in June 2015,
- Following entry into the trial, patients go on a chemotherapy holiday and enter an immunotherapy phase of treatment. A single cycle of Ad-RTS-hIL-12, along with the oral activator ligand veledimex, is given during the immunotherapy phase, with the goal of maintaining or improving pre-study response. Continuation of HER2-targeted antibody therapy is permitted during this immunotherapy phase for women with HER2+ disease. The study design allows for a review of the trial after every five subjects with HER2? and with HER2+ disease are treated. To date, five patients have been enrolled, including four with HER2- disease and one with HER2+ disease.
- • On April 27, 2015, Ziopharm Oncology announced the initiation of a Phase 1b/2 study of Ad-RTS-hIL-12 + veledimex following standard chemotherapy for the treatment of patients with locally advanced or metastatic breast cancer. The study will be conducted at the Memorial Sloan Kettering Cancer Center in New York led by principal investigator Heather L. McArthur, M.D., M.P.H., Assistant Attending Physician, Breast Medicine Service, Memorial Sloan Kettering Cancer Center. Ad-RTS-hIL-12 is a novel gene therapy candidate for the controlled expression of IL-12, an important protein for collapsing tumor stroma and stimulating an anti-cancer T cell immune response. The study is designed to examine the safety, tolerability and efficacy of Ad-RTS-hIL-12 immunotherapy in women with locally advanced or metastatic breast cancer of all subtypes. Up to 40 subjects may be enrolled in the study, including up to 20% (8 subjects) with HER2+ breast cancer. Subjects who are receiving first- or second-line standard therapy and have achieved a partial response or stable disease are eligible. Following entry into the trial, patients will go on a treatment holiday from chemotherapy and enter an immunotherapy phase of treatment. A single cycle of Ad-RTS-hIL-12, along with the oral activator ligand veledimex, will be given during the immunotherapy phase, with the goal of maintaining or improving pre-study response. Continuation of HER2-targeted antibody therapy is permitted during this immunotherapy phase for women with HER2+ disease. The primary study objective is to evaluate the safety and tolerability of Ad-RTS-hIL-12 immunotherapy. Secondary objectives include overall response rate, disease control rate and impact of treatment on tumor and serum immune biomarkers.
Is
general: Yes
