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

Study Overview
=================
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.

Official Title
-----------------
Phase I Trial of DNX-2401 for Diffuse Intrinsic Pontine Glioma Newly Diagnosed in Pediatric Patients.

Conditions
-----------------
Brainstem Glioma, Neoadjuvant Therapy

Intervention / Treatment
-----------------
* Biological: DNX-2401


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Informed consent OF PATIENT OR PARENTS Patient must be, in the investigator opinion, able to comply with all the protocol procedures. Age 1 - 18 years 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. Patient newly diagnosed of DIPG in MRI Lansky Performance Status ≥ 70 before inclusion Lesion considered by the investigator to be accessible for stereotactic biopsy. Lesion location will allow injection without entrance of virus in the ventricular system. No previous treatment for DIPG Exclusion Criteria: 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)]. Investigational medication in the previous 30 days. Subjects with immunodeficiency, autoimmune conditions or active hepatitis. 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. Tumor with multiple locations or doubt in MRI of a DIPG. 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. Severe bone marrow hypoplasia. AST (aspartate transaminase) and/or ALT (alanine transaminase)> 3 times over upper normal laboratory level Neutrophils < 1 x 109/L Thrombocytes ≤ 100 x 109/L 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.

Ages Eligible for Study
-----------------
Minimum Age: 1 Year
Maximum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: single arm treatment DNX-2401<br>Single arm receiving virus DNX-2401 infusion after tumor biopsy | Biological: DNX-2401<br>* Brain infusion of the virus through the cerebellar peduncle<br>* Other names: Delta-24;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety, tolerability and toxicity of DNX-2401 injected in the cerebellar peduncle | The trial will look for hematologic and neurologic toxicity (NCI-CTCAE v 4.03). | 12 weeks after virus injection | 

Secondary Outcome Measures

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

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Diffuse intrinsic pontine gliomas, Oncolytic adenovirus