Virus DNX2401 and Temozolomide in Recurrent Glioblastoma (D24GBM)
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.
|Glioblastoma Multiforme Recurrent Tumor||Procedure: DNX2401 and Temozolomide||Phase 1|
|Study Design:||Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|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|
- Number of participans with adverse events [ Time Frame: 3 months ]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.
- Efficacy of the combination: PFS6 and OS12 [ Time Frame: 12 months ]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 [ Time Frame: 12 months ]To assess tumor response using RANO criteria
- Quality of life [ Time Frame: 18 months ]To measure quality of life (QoL) baseline assessment and any changes over time
- Biological response [ Time Frame: 3 months ]To determine immunogenicity, biomarkers and tumor genetics
|Study Start Date:||September 2013|
|Estimated Study Completion Date:||March 2017|
|Estimated Primary Completion Date:||December 2015 (Final data collection date for primary outcome measure)|
Experimental: DNX2401 and Temozolomide
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.
Procedure: DNX2401 and Temozolomide
Virus injection in the brain parenchyma after pathology confirmation of recurrent glioblastoma.
Temozolomide oral 14 days after virus injection.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01956734
|Clinica Universidad de Navarra|
|Pamplona, Navarra, Spain, 31008|
|Principal Investigator:||Sonia Tejada, MD, PhD||Clinica Universidad de Navarra|