title: 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: BACKGROUND
  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. 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.
  
  
  METHODS
  ParvOryx01 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.
  
  
  CONCLUSIONS
  This 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.
  
  
  BACKGROUND
  ClinicalTrials.gov Identifier: NCT01301430.
authors.affiliation: Department of Neurosurgery, University Hospital Heidelberg, Germany.
authors.forename: Karsten
authors.initials: K
authors.lastname: Geletneky
authors.forename: Johannes
authors.initials: J
authors.lastname: Huesing
authors.forename: Jean
authors.initials: J
authors.lastname: Rommelaere
authors.forename: Joerg R
authors.initials: JR
authors.lastname: Schlehofer
authors.forename: Barbara
authors.initials: B
authors.lastname: Leuchs
authors.forename: Michael
authors.initials: M
authors.lastname: Dahm
authors.forename: Ottheinz
authors.initials: O
authors.lastname: Krebs
authors.forename: Magnus
authors.initials: M
authors.lastname: von Knebel Doeberitz
authors.forename: Bernard
authors.initials: B
authors.lastname: Huber
authors.forename: Jacek
authors.initials: J
authors.lastname: Hajda
mesh_terms: D061605:Administration, Intravenous; D001932:Brain Neoplasms / Q000473:pathology / Q000628:therapy*; D002985:Clinical Protocols; D018450:Disease Progression; D005260:Female; D005822:Genetic Vectors / Q000008:administration & dosage*; D005909:Glioblastoma / Q000473:pathology / Q000628:therapy*; D052661:H-1 parvovirus / Q000235:genetics*; D006801:Humans; D015552:Injections, Intralesional; D008297:Male; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics*; D012008:Recurrence