Oncolytic Adenovirus, DNX-2401, for Naive Diffuse Intrinsic Pontine Gliomas

• ClinicalTrials.gov Identifier: NCT03178032
• Recruitment Status: Unknown
• First Posted: June 6, 2017
• Last Update Posted: July 16, 2020
• Sponsor: Clinica Universidad de Navarra, Universidad de Navarra
• Collaborators: DNAtrix, Inc.; Alcyone Lifesciences, Inc.
• Information provided by (Responsible Party): Clinica Universidad de Navarra, Universidad de Navarra

Tracking Information

• First Submitted Date: June 3, 2017
• First Posted Date: June 6, 2017
• Last Update Posted Date: July 16, 2020
• Actual Study Start Date: May 26, 2017
• Estimated Primary Completion Date: January 31, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 3, 2017)

Safety, tolerability and toxicity of DNX-2401 injected in the cerebellar peduncle [ Time Frame: 12 weeks after virus injection ]

The trial will look for hematologic and neurologic toxicity (NCI-CTCAE v 4.03).

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: June 3, 2017)

• OS12 [ Time Frame: 12 months after virus injection ]
  Overall Survival at 12 months
• Images response [ Time Frame: 12 months after virus injection ]
  Complete/partial response in MRI
• QoL [ Time Frame: 12 months after virus injection ]
  measure quality of life baseline assessment and any changes over time
• Samples collection [ Time Frame: 12 weeks after virus injection ]
  Collect tumor and blood samples for futures molecular and immune studies.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Oncolytic Adenovirus, DNX-2401, for Naive Diffuse Intrinsic Pontine Gliomas
• Official Title: Phase I Trial of DNX-2401 for Diffuse Intrinsic Pontine Glioma Newly Diagnosed in Pediatric Patients.
• Brief Summary: Oncolytic adenovirus for pediatric naive DIPG, to be infused after tumor biopsy through the same trajectory in the cerebellar peduncle.
• Detailed Description: Diffuse pontine gliomas (DIPG) are one of the most lethal pediatric tumors. All treatment approaches for these tumors have failed, leaving a terrible prospect with median survival under one year, and survival at 5 years virtually of zero. Moreover, most of the long term survivors suffer from long-term side effects of the aggressive treatment. Thus, new therapeutic strategies are required that allow not only for more effective treatments of these tumors but also that defer the severe side effects derived from the current therapeutic choices. DNX-2401 is an oncolytic virus engineered to replicate specifically in tumor cells with an abnormal retinoblastoma (RB) pathway. Moreover, this virus infects cells through integrins, which are more abundant in glioma cells. Here we propose a phase I, unicentric, non-randomized clinical trial to study the safety and potential efficacy of intratumoral administration of DNX-2401 in DIPG. The virus administration will be done after stereotactic tumor biopsy, using the same trajectory, after verification of catheter position with intraoperative MRI. After 3-4 weeks patients will receive standard radiotherapy and/or chemotherapy. The primary objective is to confirm the safety of the target dose known from adults trials. Secondary endpoints are overall survival at 12 months (OS12), percentage of responses and induced immune response against tumor. The follow up includes close monitoring of neurological status, blood tests and brain MRI. If this trial shows evidence of safety and efficacy will propel a multicenter clinical trial.
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Brainstem Glioma
• Neoadjuvant Therapy

Intervention

Biological: DNX-2401

Brain infusion of the virus through the cerebellar peduncle

Other Name: Delta-24

Study Arms

Experimental: single arm treatment DNX-2401

Single arm receiving virus DNX-2401 infusion after tumor biopsy

Intervention: Biological: DNX-2401

Publications *

• Alonso MM, Gomez-Manzano C, Bekele BN, Yung WK, Fueyo J. Adenovirus-based strategies overcome temozolomide resistance by silencing the O6-methylguanine-DNA methyltransferase promoter. Cancer Res. 2007 Dec 15;67(24):11499-504.
• Jansen MH, Veldhuijzen van Zanten SE, Sanchez Aliaga E, Heymans MW, Warmuth-Metz M, Hargrave D, van der Hoeven EJ, Gidding CE, de Bont ES, Eshghi OS, Reddingius R, Peeters CM, Schouten-van Meeteren AY, Gooskens RH, Granzen B, Paardekooper GM, Janssens GO, Noske DP, Barkhof F, Kramm CM, Vandertop WP, Kaspers GJ, van Vuurden DG. Survival prediction model of children with diffuse intrinsic pontine glioma based on clinical and radiological criteria. Neuro Oncol. 2015 Jan;17(1):160-6. doi: 10.1093/neuonc/nou104. Epub 2014 Jun 5.
• Jiang H, Gomez-Manzano C, Aoki H, Alonso MM, Kondo S, McCormick F, Xu J, Kondo Y, Bekele BN, Colman H, Lang FF, Fueyo J. Examination of the therapeutic potential of Delta-24-RGD in brain tumor stem cells: role of autophagic cell death. J Natl Cancer Inst. 2007 Sep 19;99(18):1410-4. Epub 2007 Sep 11.
• Gállego Pérez-Larraya J, Garcia-Moure M, Labiano S, Patiño-García A, Dobbs J, Gonzalez-Huarriz M, Zalacain M, Marrodan L, Martinez-Velez N, Puigdelloses M, Laspidea V, Astigarraga I, Lopez-Ibor B, Cruz O, Oscoz Lizarbe M, Hervas-Stubbs S, Alkorta-Aranburu G, Tamayo I, Tavira B, Hernandez-Alcoceba R, Jones C, Dharmadhikari G, Ruiz-Moreno C, Stunnenberg H, Hulleman E, van der Lugt J, Idoate MÁ, Diez-Valle R, Esparragosa Vázquez I, Villalba M, de Andrea C, Núñez-Córdoba JM, Ewald B, Robbins J, Fueyo J, Gomez-Manzano C, Lang FF, Tejada S, Alonso MM. Oncolytic DNX-2401 Virus for Pediatric Diffuse Intrinsic Pontine Glioma. N Engl J Med. 2022 Jun 30;386(26):2471-2481. doi: 10.1056/NEJMoa2202028.
• Martínez-Vélez N, Garcia-Moure M, Marigil M, González-Huarriz M, Puigdelloses M, Gallego Pérez-Larraya J, Zalacaín M, Marrodán L, Varela-Guruceaga M, Laspidea V, Aristu JJ, Ramos LI, Tejada-Solís S, Díez-Valle R, Jones C, Mackay A, Martínez-Climent JA, García-Barchino MJ, Raabe E, Monje M, Becher OJ, Junier MP, El-Habr EA, Chneiweiss H, Aldave G, Jiang H, Fueyo J, Patiño-García A, Gomez-Manzano C, Alonso MM. The oncolytic virus Delta-24-RGD elicits an antitumor effect in pediatric glioma and DIPG mouse models. Nat Commun. 2019 May 28;10(1):2235. doi: 10.1038/s41467-019-10043-0.

Recruitment Information

• Recruitment Status: Unknown status
• Actual Enrollment (submitted: June 3, 2017): 12
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: January 31, 2021
• Estimated Primary Completion Date: January 31, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Informed consent OF PATIENT OR PARENTS
2. Patient must be, in the investigator opinion, able to comply with all the protocol procedures.
3. Age 1 - 18 years
4. Negative pregnant blood test in case of fertile women (A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
5. Patient newly diagnosed of DIPG in MRI
6. Lansky Performance Status ≥ 70 before inclusion
7. Lesion considered by the investigator to be accessible for stereotactic biopsy. Lesion location will allow injection without entrance of virus in the ventricular system.
8. No previous treatment for DIPG

Exclusion Criteria:

1. Severe infections or intercurrent medical conditions including, but not limited to, severe renal, hepatic, heart or bone marrow failure, that, on investigator´s criteria, do not allow the inclusion. Patients must be afebrile at baseline [i.e., < 38 degrees (Cº)].
2. Investigational medication in the previous 30 days.
3. Subjects with immunodeficiency, autoimmune conditions or active hepatitis.
4. Any medical or psychological condition that might interfere with the subject's ability to participate if older than 16 years or parents ability when younger than 16, or give informed consent or would compromise the patient's ability to tolerate therapy or any disease that will obscure toxicity or dangerously alter drug metabolism.
5. Tumor with multiple locations or doubt in MRI of a DIPG.
6. Pregnant or breast-feeding females will be excluded, due to the risk for the fetal development of a recombinant virus containing genes related to cellular growth and differentiation.
7. Severe bone marrow hypoplasia.
8. AST (aspartate transaminase) and/or ALT (alanine transaminase)> 3 times over upper normal laboratory level
9. Neutrophils < 1 x 109/L
10. Thrombocytes ≤ 100 x 109/L
11. Hemoglobin < 9g/dl

13. Patients with Li-Fraumeni Syndrome or with a known germ line deficit in the retinoblastoma gene or its related pathways.

14. Vaccinations of any kind within 30 days prior to DNX-2401 administration. 15. Transfusions or medications (G-CSF) to treat pancytopenia or other hematological conditions within 28 days of baseline.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 1 Year to 18 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Spain

Administrative Information

• NCT Number: NCT03178032
• Other Study ID Numbers: D24-DIPG
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: During the trail the results will be presented in scientific meetings. After the trial, a paper will be published by the IP

• Current Responsible Party: Clinica Universidad de Navarra, Universidad de Navarra
• Original Responsible Party: Sonia Tejada, Clinica Universidad de Navarra, Universidad de Navarra, MD
• Current Study Sponsor: Clinica Universidad de Navarra, Universidad de Navarra
• Original Study Sponsor: Same as current

Collaborators

• DNAtrix, Inc.
• Alcyone Lifesciences, Inc.

Investigators

• Principal Investigator: Jaime Gallego, MD, PhD; Clinica Universidad de Navarra

• PRS Account: Clinica Universidad de Navarra, Universidad de Navarra
• Verification Date: July 2020