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

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

Molecular Pathways: Rodent Parvoviruses—Mechanisms of Oncolysis and Prospects for Clinical Cancer Treatment

“…Preclinical evidence of strong cytotoxic and oncosuppressive effects of H-1PV against glioma cells led to the launch in October 2011 of a first phase I/IIa study of H-1PV in patients with recurrent GBM [ParvOryx 01; ClinicalTrials.gov, identifier NCT01301430). ParvOryx 01 is an open, noncontrolled, dose-escalation, single-center trial (47). H-1PV is administered before resection by either the intratumoral or the intravenous route, and again into the walls of the tumor cavity during tumor removal.…”

Cell cycle S phase markers are expressed in cerebral neuron nuclei of cats infected by the Feline Panleukopenia Virus

“…31 The safety studies did not disclose specific risk. 32 However, our results also raises questions about the use of parvoviruses as anti-cancer weapon in their natural target species.…”

Activation of the human immune system via toll‐like receptors by the oncolytic parvovirus H‐1

“…7,[22][23][24] Furthermore, the death mechanisms activated by PVs allow them to circumvent resistance of tumor cells to conventional death inducers 10,25 and preclinical data on efficacy and safety produced proofs of concept leading to the recent launching of a phase I/IIa clinical trial. 26 Dendritic cells play an important role in this, linking the innate with adaptive immune responses. 27,28 Activation of dendritic cells and tumor infiltration with natural killer cells are typical signs of immune system activation following cellular infection by H-1PV.…”