A non-controlled, single arm, open label, phase II study of intravenous and intratumoral administration of ParvOryx in patients with metastatic, inoperable pancreatic cancer: ParvOryx02 protocol

Abstract

BackgroundMetastatic pancreatic cancer has a dismal prognosis, with a mean six-month progression-free survival of approximately 50% and a median survival of about 11 months. Despite intensive research, only slight improvements of clinical outcome could be achieved over the last decades. Hence, new and innovative therapeutic strategies are urgently required. ParvOryx is a drug product containing native parvovirus H-1 (H-1PV). Since H-1PV was shown to exert pronounced anti-neoplastic effects in pre-clinical models of pancreatic cancer, the drug appears to be a promising candidate for treatment of this malignancy.MethodsParvOryx02 is a non-controlled, single arm, open label, dose-escalating, single center trial. In total seven patients with pancreatic cancer showing at least one hepatic metastasis are to be treated with escalating doses of ParvOryx according to the following schedule: i) 40% of the total dose infused intravenously in equal fractions on four consecutive days, ii) 60% of the total dose injected on a single occasion directly into the hepatic metastasis at varying intervals after intravenous infusions. The main eligibility criteria are: age ≥ 18 years, disease progression despite first-line chemotherapy, and at least one hepatic metastasis. Since it is the second trial within the drug development program, the study primarily explores safety and tolerability after further dose escalation of ParvOryx. The secondary objectives are related to the evaluation of certain aspects of anti-tumor activity and clinical efficacy of the drug.DiscussionThis trial strongly contributes to the clinical development program of ParvOryx. The individual hazards for patients included in the current study and the environmental risks are addressed and counteracted adequately. Besides information on safety and tolerability of the treatment after further dose escalation, thorough evaluations of pharmacokinetics and intratumoral spread as well as proof-of-concept (PoC) in pancreatic cancer will be gained in the course of the trial.Trial registrationClinicalTrials.gov-ID: NCT02653313, Registration date: Dec. 4th, 2015.

Preclinical Testing of an Oncolytic Parvovirus in Ewing Sarcoma: Protoparvovirus H-1 Induces Apoptosis and Lytic Infection In Vitro but Fails to Improve Survival In Vivo

“…Signs of an immune response, such as infiltration of the infected tumors with cytotoxic T-cells, provided first evidence of the capacity of the virus to recruit the immune system of the host to induce an antitumor immune response [ 18 ]. On the basis of these promising safety data, a second trial, on pancreatic adenocarcinoma patients, has been initiated [ 19 ].…”

Mutations in the Non-Structural Protein-Coding Sequence of Protoparvovirus H-1PV Enhance the Fitness of the Virus and Show Key Benefits Regarding the Transduction Efficiency of Derived Vectors

“…Recently, the first phase I/IIa clinical trial in which wild-type H-1PV was administered to recurrent glioblastoma patients [ 24 ] has provided promising results allowing further H-1PV clinical investigation, not only in glioblastoma patients but also in patients with metastatic pancreatic cancer [ 36 ]. However, the efficacy of H-1PV might be limited by the fact that the rodent protoparvovirus does not usually propagate in human tumor cells and, consequently, there is a need to optimize such viral therapeutics.…”

Delivery and Biosafety of Oncolytic Virotherapy

“…Preclinical studies of H-1PV showed that H-1PV induces embryonic and fetal toxicity in rodents and harmful effects on progeny, usually leading to the death of a fetus infected during the second trimester. When pregnant women are infected in the third trimester or a few days before birth, the progeny often develop "osteolytic syndrome" characterized by dwarfism and various down syndrome-like features (120,121). Cancer patients who received radiotherapy and chemotherapy usually show low immunity to virus infection.…”