Virus Therapy for Brain Tumors
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: M.D. Anderson Cancer Center
Must not be taking: Anticoagulants, Immunosuppressants
Disqualifiers: Pregnancy, Infection, Autoimmune disorders, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This phase I trial studies best dose and side effects of oncolytic adenovirus DNX-2401 in treating patients with high-grade glioma that has come back (recurrent). Oncolytic adenovirus DNX-2401 is made from the common cold virus that has been changed in the laboratory to make it less likely to cause an infection (such as a cold). The virus is also changed to target brain cancer cells and attack them.
Will I have to stop taking my current medications?
The trial requires participants to stop taking other cytotoxic and non-cytotoxic drugs or radiation therapy against the tumor while enrolled. Additionally, there are specific time periods that must be observed after completing certain chemotherapies before starting the trial.
What data supports the effectiveness of the treatment DNX-2401 for brain tumors?
Research shows that DNX-2401, an oncolytic virus, can help some patients with brain tumors live longer by directly attacking tumor cells and boosting the body's immune response against the tumor. In studies, some patients with recurrent malignant glioma experienced significant tumor reduction and long-term survival, and the treatment was found to be safe in both adults and children.
12345Is DNX-2401 safe for use in humans?
DNX-2401 has been tested in clinical trials for brain tumors and has shown a favorable safety profile, with no dose-limiting toxicities reported. It has been well tolerated in both adults and children, with some patients experiencing long-term survival.
12346What makes the treatment DNX-2401 unique for brain tumors?
DNX-2401 is unique because it is an oncolytic virus, meaning it is a virus designed to selectively infect and kill cancer cells while sparing normal cells. It works by directly destroying tumor cells and stimulating the body's immune system to attack the tumor, offering a novel approach compared to traditional treatments like chemotherapy or radiation.
12345Eligibility Criteria
Adults with recurrent high-grade glioma, such as glioblastoma or astrocytoma, who have tried surgery, chemotherapy, or radiation before. They must be in good enough health to undergo endovascular treatment and have a life expectancy of at least 16 weeks. Participants need a tumor size between 1-5 cm and a Karnofsky score ≥70 (able to care for themselves). Pregnant women are excluded.Inclusion Criteria
My tumor can be removed surgically, and I need a surgery to remove part of my skull to access it.
My recurrent brain tumor does not have IDH-1 mutation and shows a significant mass on MRI.
It has been at least 8 weeks since my last radiotherapy session.
+16 more
Exclusion Criteria
My cancer has spread to the lining of my brain and spinal cord.
I have trouble getting IV lines placed for procedures.
I haven't had biologic or immunotherapy in the last 2 weeks.
+20 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment Part I
Patients receive one or two infusions of BM-hMSCs-DNX-2401 intra-arterially over 20-30 minutes on day 0. Dose level 1-5 will receive 1 infusion. Dose level 6 will receive 2 infusions.
1 day
1 visit (in-person)
Treatment Part II
Patients receive one or two infusions of BM-hMSCs-DNX-2401 IA, depending on the highest dose tolerated in Part 1. After 2 weeks, patients undergo surgery where the tumor is removed, then receive intramural injection of BM-hMSCs-DNX-2401 into the resection cavity.
2 weeks
1 visit (in-person) for surgery
Follow-up
Participants are monitored for safety and effectiveness after treatment. Follow-up occurs on days 1, 4, 7, and 14 of month 1, every 6 weeks for 6 months, then every 8 weeks for 1 year, then every 4 months for 1 year, then every 6 months until the tumor grows back.
Up to 2 years
Multiple visits (in-person)
Participant Groups
The trial is testing the safety and optimal dose of DNX-2401, an altered cold virus targeting brain cancer cells. It's given after conventional surgery to see if it can help treat recurrent high-grade gliomas more effectively than current treatments.
2Treatment groups
Experimental Treatment
Group I: Part II (oncolytic adenovirus Ad5-DNX-2401, surgery)Experimental Treatment2 Interventions
Patients receive oncolytic adenovirus Ad5-DNX-2401 as in part I. After 2 weeks, patients undergo surgery, then receive oncolytic adenovirus Ad5-DNX-2401 IA over 20-30 minutes.
Group II: Part I (oncolytic adenovirus Ad5-DNX-2401)Experimental Treatment1 Intervention
Patients receive oncolytic adenovirus Ad5-DNX-2401 IA over 20-30 minutes on day 0.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
M D Anderson Cancer CenterHouston, TX
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Who Is Running the Clinical Trial?
M.D. Anderson Cancer CenterLead Sponsor
DNAtrix, Inc.Industry Sponsor
References
Phase I Study of DNX-2401 (Delta-24-RGD) Oncolytic Adenovirus: Replication and Immunotherapeutic Effects in Recurrent Malignant Glioma. [2023]Purpose DNX-2401 (Delta-24-RGD; tasadenoturev) is a tumor-selective, replication-competent oncolytic adenovirus. Preclinical studies demonstrated antiglioma efficacy, but the effects and mechanisms of action have not been evaluated in patients. Methods A phase I, dose-escalation, biologic-end-point clinical trial of DNX-2401 was conducted in 37 patients with recurrent malignant glioma. Patients received a single intratumoral injection of DNX-2401 into biopsy-confirmed recurrent tumor to evaluate safety and response across eight dose levels (group A). To investigate the mechanism of action, a second group of patients (group B) underwent intratumoral injection through a permanently implanted catheter, followed 14 days later by en bloc resection to acquire post-treatment specimens. Results In group A (n = 25), 20% of patients survived > 3 years from treatment, and three patients had a ≥ 95% reduction in the enhancing tumor (12%), with all three of these dramatic responses resulting in > 3 years of progression-free survival from the time of treatment. Analyses of post-treatment surgical specimens (group B, n = 12) showed that DNX-2401 replicates and spreads within the tumor, documenting direct virus-induced oncolysis in patients. In addition to radiographic signs of inflammation, histopathologic examination of immune markers in post-treatment specimens showed tumor infiltration by CD8+ and T-bet+ cells, and transmembrane immunoglobulin mucin-3 downregulation after treatment. Analyses of patient-derived cell lines for damage-associated molecular patterns revealed induction of immunogenic cell death in tumor cells after DNX-2401 administration. Conclusion Treatment with DNX-2401 resulted in dramatic responses with long-term survival in recurrent high-grade gliomas that are probably due to direct oncolytic effects of the virus followed by elicitation of an immune-mediated antiglioma response.
Oncolytic DNX-2401 virotherapy plus pembrolizumab in recurrent glioblastoma: a phase 1/2 trial. [2023]Immune-mediated anti-tumoral responses, elicited by oncolytic viruses and augmented with checkpoint inhibition, may be an effective treatment approach for glioblastoma. Here in this multicenter phase 1/2 study we evaluated the combination of intratumoral delivery of oncolytic virus DNX-2401 followed by intravenous anti-PD-1 antibody pembrolizumab in recurrent glioblastoma, first in a dose-escalation and then in a dose-expansion phase, in 49 patients. The primary endpoints were overall safety and objective response rate. The primary safety endpoint was met, whereas the primary efficacy endpoint was not met. There were no dose-limiting toxicities, and full dose combined treatment was well tolerated. The objective response rate was 10.4% (90% confidence interval (CI) 4.2-20.7%), which was not statistically greater than the prespecified control rate of 5%. The secondary endpoint of overall survival at 12 months was 52.7% (95% CI 40.1-69.2%), which was statistically greater than the prespecified control rate of 20%. Median overall survival was 12.5 months (10.7-13.5 months). Objective responses led to longer survival (hazard ratio 0.20, 95% CI 0.05-0.87). A total of 56.2% (95% CI 41.1-70.5%) of patients had a clinical benefit defined as stable disease or better. Three patients completed treatment with durable responses and remain alive at 45, 48 and 60 months. Exploratory mutational, gene-expression and immunophenotypic analyses revealed that the balance between immune cell infiltration and expression of checkpoint inhibitors may potentially inform on response to treatment and mechanisms of resistance. Overall, the combination of intratumoral DNX-2401 followed by pembrolizumab was safe with notable survival benefit in select patients (ClinicalTrials.gov registration: NCT02798406).
DNX-2401, an Oncolytic Virus, for the Treatment of Newly Diagnosed Diffuse Intrinsic Pontine Gliomas: A Case Report. [2020]Diffuse intrinsic pontine gliomas (DIPGs) are aggressive glial brain tumors that primarily affect children, for which there is no curative treatment. Median overall survival is only one year. Currently, the scientific focus is on expanding the knowledge base of the molecular biology of DIPG, and identifying effective therapies. Oncolytic adenovirus DNX-2401 is a replication-competent, genetically modified virus capable of infecting and killing glioma cells, and stimulating an anti-tumor immune response. Clinical trials evaluating intratumoral DNX-2401 in adults with recurrent glioblastoma have demonstrated that the virus has a favorable safety profile and can prolong survival. Subsequently, these results have encouraged the transition of this biologically active therapy from adults into the pediatric population. To this aim, we have designed a clinical Phase I trial for newly diagnosed pediatric DIPG to investigate the feasibility, safety, and preliminary efficacy of delivering DNX-2401 into tumors within the pons following biopsy. This case report presents a pediatric patient enrolled in this ongoing Phase I trial for children and adolescents with newly diagnosed DIPG. The case involves an 8-year-old female patient with radiologically diagnosed DIPG who underwent stereotactic tumor biopsy immediately followed by intratumoral DNX-2401 in the same biopsy track. Because there were no safety concerns or new neurological deficits, the patient was discharged 3 days after the procedures. To our knowledge, this is the first report of intratumoral DNX-2401 for a patient with DIPG in a clinical trial. We plan to demonstrate that intratumoral delivery of an oncolytic virus following tumor biopsy for pediatric patients with DIPG is a novel and feasible approach and that DNX-2401 represents an innovative treatment for the disease.
Delta-24 adenoviral therapy for glioblastoma: evolution from the bench to bedside and future considerations. [2021]Delta-24-based oncolytic viruses are conditional replication adenoviruses developed to selectively infect and replicate in retinoblastoma 1 (Rb)-deficient cancer cells but not normal cell with intact Rb1 pathways. Over the years, there has been a significant evolution in the design of Delta-24 based on a better understanding of the underlying basis for infection, replication, and spread within cancer. One example is the development of Delta-24-RGD (DNX-2401), where the arginine-glycine-aspartate (RGD) domain enhances the infectivity of Delta-24 for cancer cells. DNX-2401 demonstrated objective biological and clinical responses during a phase I window of opportunity clinical trial for recurrent human glioblastoma. In long-term responders (> 3 years), there was evidence of immune infiltration (T cells and macrophages) into the tumor microenvironment with minimal toxicity. Although more in-depth analysis and phase III studies are pending, these results indicate that Delta-24-based adenovirus therapy may induce an antitumor response in glioblastoma, resulting in long-term antitumor immune response. In this review, the authors discuss the preclinical and clinical development of Delta-24 oncolytic adenoviral therapy for glioblastoma and describe structural improvements to Delta-24 that have enhanced its efficacy in vivo. They also highlight ongoing research that attempts to address the remaining obstacles limiting efficacy of Delta-24 adenovirus therapy for glioblastoma.
The oncolytic virus Delta-24-RGD elicits an antitumor effect in pediatric glioma and DIPG mouse models. [2021]Pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors in desperate need of a curative treatment. Oncolytic virotherapy is emerging as a solid therapeutic approach. Delta-24-RGD is a replication competent adenovirus engineered to replicate in tumor cells with an aberrant RB pathway. This virus has proven to be safe and effective in adult gliomas. Here we report that the administration of Delta-24-RGD is safe in mice and results in a significant increase in survival in immunodeficient and immunocompetent models of pHGG and DIPGs. Our results show that the Delta-24-RGD antiglioma effect is mediated by the oncolytic effect and the immune response elicited against the tumor. Altogether, our data highlight the potential of this virus as treatment for patients with these tumors. Of clinical significance, these data have led to the start of a phase I/II clinical trial at our institution for newly diagnosed DIPG (NCT03178032).
Oncolytic virotherapy for the treatment of pediatric brainstem gliomas. [2023]Diffuse intrinsic pontine glioma (DIPG) is the most frequent brainstem glioma and the most lethal brain tumor in childhood. Despite transient benefit with radiotherapy, the prognosis of children with this disease remains dismal with severe neurological morbidity and median survival less than 12months. Oncolytic immunovirotherapy is emerging as a potential therapeutic approach in neuro-oncology. The oncolytic adenovirus Delta-24-RGD has shown efficacy in adult patients with recurrent GBM. Our group has demonstrated that Delta-24-RGD has oncolytic activity and triggers immune response in preclinical models of DIPG, and has a synergistic effect with radiotherapy in animal models of this disease. In this scenario, we conducted a first-in-human phase 1 clinical trial to evaluate the safety and efficacy of intratumoral injection of Delta-24-RGD in pediatric patients with newly diagnosed DIPG prior to standard radiotherapy. The study confirmed the feasibility of this treatment with an acceptable safety profile and encouraging efficacy results. Correlative analyses showed a biological activity from Delta-24-RGD in DIPG. Further advanced trials are needed to validate these results. Meanwhile, plenty of opportunities to increase the potential contribution of oncolytic viruses in the management of devastating tumors with no current effective treatment such as DIPG need to be explored and exploited.