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Virus DNX2401 and Temozolomide in Recurrent Glioblastoma (D24GBM)

Primary Purpose

Glioblastoma Multiforme, Recurrent Tumor

Status

Completed

Phase

Phase 1

Locations

Spain

Study Type

Interventional

Intervention

DNX2401 and Temozolomide

About this trial

This is an interventional treatment trial for Glioblastoma Multiforme focused on measuring glioblastoma, first recurrence, temozolomide

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria:

Patients willing and able to give informed consent and willing to comply with all the protocol procedures.
Patient must be, in the investigator opinion, able to comply with all the protocol procedures.
Age 18-75 years.
Negative pregnant test in case of fertile women.
Patient diagnosed GBM in first recurrence after radiotherapy and TMZ. Must have completed at least radiotherapy and one TMZ cycle afterwards.
Intraoperative histological verification of recurrence is needed to confirm inclusion.
Karnofsky Performance Status ≥ 70 before inclusion
Lesion considered by the investigator to be resectable or accessible for stereotactic biopsy. Lesion location will allow injection without entrance of virus in the ventricular system.
Last TMZ cycle must have been finished at least 4 weeks before entry in the study.
Must have adequate renal, bone marrow and liver function.

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.
Participation on another clinical trial in the previous 30 days.
Previous hypersensitivity to temozolomide or any associated components. Previous serious toxicity to temozolomide.
Subjects with immunodeficiency, autoimmune conditions or active hepatitis.
Any medical or psychological condition that might interfere with the subject's ability to participate or give informed consent.
Tumor with multiple locations, unless all the lesions are considered resectable, or all the lesions except one can be resected, and the last one can be injected; diffuse subependymal spreading or location that would need injection through ventricle.
Current diagnosis of other cancer except in situ cervical cancer, basal or squamous cell carcinoma of the skin. Patients with a history of another cancer remain eligible if they are cancer free for at least three years.
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.
Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) > 3 times over normal laboratory level.

Sites / Locations

Clinica Universidad de Navarra

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

DNX2401 and Temozolomide

Arm Description

DNX2401: Virus injection in the brain parenchyma. Total dose will be 3x1010 vp suspended in 1 ml for all cases. Temozolomide: 14 (window 14-28 days) days after the virus injection, patients will begin therapy with temozolomide in a dose of 150mg/m2 in days 1-7 and 15 -21 of a 28 days cycle, (dose dense scheme 7 days on, 7 days off), until a maximum of 2 x 28 days cycles in absence of toxicity.

Outcomes

Primary Outcome Measures

Number of participans with adverse events

Tolerance of the combination of DNX-2401 and temozolomide will be evaluated through neurological and hematological status. Any toxicity will be graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTCAE) version 4.03.

Secondary Outcome Measures

Efficacy of the combination: PFS6 and OS12

To determine, using the Revised Assessment in Neuro-Oncology (RANO) criteria, time to disease progression, progression-free survival at 6 months (PFS6), median progression-free survival, overall survival at 12 months (OS12) and median overall survival following intratumoral or intramural injection of DNX-2401 and two cycles of temozolomide

Tumor response

To assess tumor response using RANO criteria

Quality of life

To measure quality of life (QoL) baseline assessment and any changes over time

Biological response

To determine immunogenicity, biomarkers and tumor genetics

Full Information

NCT ID

NCT01956734

First Posted

September 27, 2013

Last Updated

October 23, 2017

Sponsor

Clinica Universidad de Navarra, Universidad de Navarra

Collaborators

DNAtrix, Inc.

1. Study Identification

Unique Protocol Identification Number

NCT01956734

Brief Title

Virus DNX2401 and Temozolomide in Recurrent Glioblastoma

Acronym

D24GBM

Official Title

Phase I Trial of Combination of DNX-2401 (Formerly Named Delta-24-RGD) Oncolytic Adenovirus With a Short Course of Temozolomide for Treatment of Glioblastoma at First Recurrent

Study Type

Interventional

2. Study Status

Record Verification Date

June 2017

Overall Recruitment Status

Completed

Study Start Date

September 2013 (Actual)

Primary Completion Date

December 2015 (Actual)

Study Completion Date

March 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Clinica Universidad de Navarra, Universidad de Navarra

Collaborators

DNAtrix, Inc.

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Phase I trial, unicentric, uncontrolled. Intratumoral injection or intramural (into the resected tumor cavity) of DNX2401 into brain tissue will be followed by up to two 28 - day cycles of oral temozolomide (TMZ) in schedule of 7 days on/7 days off to evaluate safety of the combination. Completion of two full cycles of TMZ will be dependent upon tolerance and toxicity. The rationale in using the virus with chemotherapy begins with the lessons learned in many clinical trials in glioblastoma (GBM) about both the great difficulty of treating this disease with monotherapy and the limitations of the therapeutic virus. The best clinical results in recent years have been achieved with combinations of multiple therapeutics efforts, including, maximum resection and chemotherapy, immunotherapy and targeted therapies. There are very strong preclinical data about the synergy of DNX-2401 and TMZ proposed in our trial design. The dose-dense schemes of TMZ like the one we will use, have been developed with the aim to saturate o6-methylguanine-DNA-methyltransferase (MGMT). The published results to date have shown reasonable toxicity albeit with modest efficacy' these schemes are now in phase III trials. In addition, autophagy triggered by TMZ could help viral replication in the tumor cells 11. The last argument in favor of this virus + TMZ combination is the proved efficacy in killing GBM tumor stem cells. In vitro and animals models have shown this combination is much more effective that any of the treatments alone against GBM stem cells and the tumors derived from them.

Detailed Description

DNX2401 will be injected after stereotactic biopsy reveals intraoperative pathology confirming the presence of recurrent glioblastoma. The injection will be either intratumoral or intramural with injections throughout the post-resection cavity.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Glioblastoma Multiforme, Recurrent Tumor

Keywords

glioblastoma, first recurrence, temozolomide

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

31 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

DNX2401 and Temozolomide

Arm Type

Experimental

Arm Description

Intervention Type

Procedure

Intervention Name(s)

DNX2401 and Temozolomide

Intervention Description

Virus injection in the brain parenchyma after pathology confirmation of recurrent glioblastoma. Temozolomide oral 14 days after virus injection.

Primary Outcome Measure Information:

Title

Number of participans with adverse events

Description

Time Frame

3 months

Secondary Outcome Measure Information:

Title

Efficacy of the combination: PFS6 and OS12

Description

Time Frame

12 months

Title

Tumor response

Description

To assess tumor response using RANO criteria

Time Frame

12 months

Title

Quality of life

Description

To measure quality of life (QoL) baseline assessment and any changes over time

Time Frame

18 months

Title

Biological response

Description

To determine immunogenicity, biomarkers and tumor genetics

Time Frame

3 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion criteria: Patients willing and able to give informed consent and willing to comply with all the protocol procedures. Patient must be, in the investigator opinion, able to comply with all the protocol procedures. Age 18-75 years. Negative pregnant test in case of fertile women. Patient diagnosed GBM in first recurrence after radiotherapy and TMZ. Must have completed at least radiotherapy and one TMZ cycle afterwards. Intraoperative histological verification of recurrence is needed to confirm inclusion. Karnofsky Performance Status ≥ 70 before inclusion Lesion considered by the investigator to be resectable or accessible for stereotactic biopsy. Lesion location will allow injection without entrance of virus in the ventricular system. Last TMZ cycle must have been finished at least 4 weeks before entry in the study. Must have adequate renal, bone marrow and liver function. 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. Participation on another clinical trial in the previous 30 days. Previous hypersensitivity to temozolomide or any associated components. Previous serious toxicity to temozolomide. Subjects with immunodeficiency, autoimmune conditions or active hepatitis. Any medical or psychological condition that might interfere with the subject's ability to participate or give informed consent. Tumor with multiple locations, unless all the lesions are considered resectable, or all the lesions except one can be resected, and the last one can be injected; diffuse subependymal spreading or location that would need injection through ventricle. Current diagnosis of other cancer except in situ cervical cancer, basal or squamous cell carcinoma of the skin. Patients with a history of another cancer remain eligible if they are cancer free for at least three years. 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. Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) > 3 times over normal laboratory level.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Sonia Tejada, MD, PhD

Organizational Affiliation

Clinica Universidad de Navarra

Official's Role

Principal Investigator

Facility Information:

Facility Name

Clinica Universidad de Navarra

City

Pamplona

State/Province

Navarra

ZIP/Postal Code

31008

Country

Spain

12. IPD Sharing Statement

Citations:

PubMed Identifier

10644974

Citation

Fueyo J, Gomez-Manzano C, Alemany R, Lee PS, McDonnell TJ, Mitlianga P, Shi YX, Levin VA, Yung WK, Kyritsis AP. A mutant oncolytic adenovirus targeting the Rb pathway produces anti-glioma effect in vivo. Oncogene. 2000 Jan 6;19(1):2-12. doi: 10.1038/sj.onc.1203251. Erratum In: Oncogene 2000 Oct 12;19(43):5038.

Results Reference

background

PubMed Identifier

19860656

Citation

Jiang H, Gomez-Manzano C, Lang FF, Alemany R, Fueyo J. Oncolytic adenovirus: preclinical and clinical studies in patients with human malignant gliomas. Curr Gene Ther. 2009 Oct;9(5):422-7. doi: 10.2174/156652309789753356.

Results Reference

background

PubMed Identifier

18089777

Citation

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. doi: 10.1158/0008-5472.CAN-07-5312.

Results Reference

background

PubMed Identifier

17134363

Citation

Jiang H, Alonso MM, Gomez-Manzano C, Piao Y, Fueyo J. Oncolytic viruses and DNA-repair machinery: overcoming chemoresistance of gliomas. Expert Rev Anticancer Ther. 2006 Nov;6(11):1585-92. doi: 10.1586/14737140.6.11.1585.

Results Reference

background

Links:

URL

http://www.cun.es/la-clinica/noticia/nuevo-ensayo-clinico-probara-tratamiento-tumores-cerebrales-mas-agresivos-virus-modificado-geneticam

Description

Hospital where the clinical trial is performed

Learn more about this trial

Virus DNX2401 and Temozolomide in Recurrent Glioblastoma

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