Phase I/IIa study of intratumoral/intracerebral or intravenous/intracerebral administration of Parvovirus H-1 (ParvOryx) in patients with progressive primary or recurrent glioblastoma multiforme: ParvOryx01 protocol

Karsten Geletneky,Jacek Hajda,Barbara Leuchs,Michael Dahm,Ottheinz Krebs,Jean Rommelaere,Bernard Huber,Joerg R Schlehofer,Magnus Von Knebel Doeberitz,Johannes Huesing

doi:10.1186/1471-2407-12-99

Abstract

BackgroundThe treatment of patients with malignant brain tumors remains a major oncological problem. The median survival of patients with glioblastoma multiforme (GBM), the most malignant type, is only 15 months after initial diagnosis and even less after tumor recurrence. Improvements of standard treatment including surgery and radio-chemotherapy have not lead to major improvements. Therefore, alternative therapeutics such as oncolytic viruses that specifically target and destroy cancer cells are under investigation. Preclinical data of oncolytic parvovirus H-1 (H-1PV) infection of glioma cells demonstrated strong cytotoxic and oncosuppressing effects, leading to a phase I/IIa trial of H-1PV in patients with recurrent GBM (ParvOryx01). ParvOryx01 is the first trial with a replication competent oncolytic virus in Germany.MethodsParvOryx01 is an open, non-controlled, two groups, intra-group dose escalation, single center, phase I/IIa trial. 18 patients with recurrent GBM will be treated in 2 groups of 9 patients each. Treatment group 1 will first receive H-1PV by intratumoral injection and second by administration into the walls of the tumor cavity during tumor resection. In treatment group 2 the virus will initially be injected intravenously and afterwards, identical to group 1, into the surrounding brain tissue during tumor removal. Main eligibility criteria are: age of 18 years, unifocal recurrent GBM, amenable to complete or subtotal resection. Dose escalation will be based on the Continual Reassessment Method. The primary objective of the trial is local and systemic safety and tolerability and to determine the maximum tolerated dose (MTD). Secondary objectives are proof of concept (PoC) and Progression-free Survival (PFS) up to 6 months.DiscussionThis is the first trial with H-1PV in patients with recurrent GBM. The risks for the participants appear well predictable and justified. Furthermore, ParvOryx01 will be the first assessment of combined intratumoral and intravenous application of an oncolytic virus. Due to its study design the trial will not only generate data on the local effect of H-1PV but it will also investigate the penetration of H-1PV into the tumor after systemic delivery and obtain safety data from systemic delivery possibly supporting clinical trials with H-1PV in other, non-CNS malignancies.Trial registrationClinicalTrials.gov Identifier: NCT01301430

Highlights

The treatment of patients with malignant brain tumors remains a major oncological problem
Even though toxicological testing of the study medication did not reveal any safety issues after intracerebral or intravenous injection, the risk of side effects or adverse events in patients has to be minimized. To meet this demand the first 3 patients in both treatment groups will receive a low virus dose and even within each dose group patients can only be included after an extended observation period of 28 days between patient 1 and 2 and 18 days between patient 2 and 3
The ParvOryx trial offers to patients the standard level of care by tumor removal in combination with the chance of oncolytic activity of the Investigational Medicinal Product (IMP)

Summary

Introduction

The treatment of patients with malignant brain tumors remains a major oncological problem. The median survival of patients with glioblastoma multiforme (GBM), the most malignant type, is only 15 months after initial diagnosis and even less after tumor recurrence. Improvements of standard treatment including surgery and radio-chemotherapy have not lead to major improvements. Alternative therapeutics such as oncolytic viruses that target and destroy cancer cells are under investigation. The largest group with approximately 12,700 new cases per year are gliomas, primary central nervous system neoplasms with characteristics of neuroglial cells. Of those the most frequent subgroup with more than 6,000 new diagnoses per year is glioblastoma multiforme (GBM), which is the most malignant type of gliomas. New approaches are on the way [5]

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