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

Study Description

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Brief Summary:

Oncolytic adenovirus for pediatric naive DIPG, to be infused after tumor biopsy through the same trajectory in the cerebellar peduncle.

Condition or disease	Intervention/treatment	Phase
Brainstem Glioma; Neoadjuvant Therapy	Biological: DNX-2401	Phase 1

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 Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	12 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Phase I Trial of DNX-2401 for Diffuse Intrinsic Pontine Glioma Newly Diagnosed in Pediatric Patients.
Actual Study Start Date :	May 30, 2017
Estimated Primary Completion Date :	August 30, 2019
Estimated Study Completion Date :	December 30, 2019

Arms and Interventions

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Arm	Intervention/treatment
Experimental: single arm treatment DNX-2401; Single arm receiving virus DNX-2401 infusion after tumor biopsy	Biological: DNX-2401; Brain infusion of the virus through the cerebellar peduncle; Other Name: Delta-24

Outcome Measures

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Primary Outcome Measures :

1. 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).

Secondary Outcome Measures :

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

Eligibility Criteria

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Ages Eligible for Study:	1 Year to 18 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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.

Contacts and Locations

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Contacts

Contact: Sonia Tejada, MD, PhD	0034948255400 ext 4590	stejada@unav.es
Contact: Jose M Galindo	0034948255400 ext 2527	jgalindom@unav.es

Locations

Spain
Clinica Universidad de Navarra	Recruiting
Pamplona, Navarra, Spain, 31190
Contact: Sonia Tejada, MD, PhD 948255400 ext 4590 stejada@unav.es
Contact: Jose Maria Galindo 948255400 ext 2527 jgalindom@unav.es
Sub-Investigator: Ricardo Diez Valle, MD, PhD
Sub-Investigator: Marta Alonso, PhD
Sub-Investigator: Ana Patiño, PhD
Sub-Investigator: Maite Garriz, MD
Sub-Investigator: Miriam Giraldez, PhD
Principal Investigator: Sonia Tejada, MD, PhD

Sponsors and Collaborators

Clinica Universidad de Navarra, Universidad de Navarra

DNAtrix, Inc.

Alcyone Lifesciences, Inc.

Investigators

Principal Investigator:	Sonia Tejada, MD, PhD	Clinica Universidad de Navarra

More Information

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Publications of Results:

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.

Responsible Party:	Sonia Tejada, MD, Clinica Universidad de Navarra, Universidad de Navarra
ClinicalTrials.gov Identifier:	NCT03178032 History of Changes
Other Study ID Numbers:	D24-DIPG
First Posted:	June 6, 2017
Last Update Posted:	June 6, 2017
Last Verified:	June 2017
Individual Participant Data (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

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

Keywords provided by Sonia Tejada, Clinica Universidad de Navarra, Universidad de Navarra:

Diffuse intrinsic pontine gliomas; Oncolytic adenovirus

Additional relevant MeSH terms:

Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal	Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue