TREAT

PI
Prof. Andreas Unterberg. Dept. of Neurosurgery Clinics, University Hospital Heidelberg

Trial ID, start of recruitment and status
NCT01301430, 2011, completed & published

Contributing CCU members
Karsten Geletneky (CCU-associated), Barbara Leuchs (CCU-associated), Jean Rommelaere, Assia Angelova

Oncolytic virotherapy may be a means of improving the dismal prognosis of malignant brain tumors. The rat H-1 parvovirus (H-1PV) suppresses tumors in preclinical glioma models, through both direct oncolysis and stimulation of anticancer immune responses. This was the basis of ParvOryx01, the first phase I/IIa clinical trial of an oncolytic parvovirus in recurrent glioblastoma patients. H-1PV (escalating dose) was administered via intratumoral or intravenous injection. Tumors were resected 9 days after treatment, and virus was re-administered around the resection cavity. Primary endpoints were safety and tolerability, virus distribution, and maximum tolerated dose (MTD). Progression-free and overall survival and levels of viral and immunological markers in the tumor and peripheral blood were also investigated. H-1PV treatment was safe and well tolerated, and no MTD was reached. The virus could cross the blood-brain/tumor barrier and spread widely through the tumor. It showed favorable pharmacokinetics, induced antibody formation in a dose-dependent manner, and triggered specific T cell responses. Markers of virus replication, microglia/macrophage activation, and cytotoxic T cell infiltration were detected in infected tumors, suggesting that H-1PV may trigger an immunogenic stimulus. Median survival was extended in comparison with recent meta-analyses. Altogether, ParvOryx01 results provide an impetus for further H-1PV clinical development. (from Geletneky et al., Mol Ther 2017, Cell Press, under the terms of Creative Commons Attribution 4.0 International License (CC BY 4.0)).

The ParvOryx01 study was the first clinical study on oncolytic parvoviruses and the first clinical study in Germany to explore virotherapy.

Publications

• Oncolytic H-1 Parvovirus Shows Safety and Signs of Immunogenic Activity in a First Phase I/IIa Glioblastoma Trial.
  Geletneky K, Hajda J, Angelova AL, Leuchs B, Capper D, Bartsch AJ, Neumann JO, Schöning T, Hüsing J, Beelte B, Kiprianova I, Roscher M, Bhat R, von Deimling A, Brück W, Just A, Frehtman V, Löbhard S, Terletskaia-Ladwig E, Fry J, Jochims K, Daniel V, Krebs O, Dahm M, Huber B, Unterberg A, Rommelaere J. Mol Ther. 2017 Dec 6;25(12):2620-2634.
• 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.
  Geletneky K, Huesing J, Rommelaere J, Schlehofer JR, Leuchs B, Dahm M, Krebs O, von Knebel Doeberitz M, Huber B, Hajda J. BMC Cancer 2012 Mar 21;12:99.

Sponsor/Funding
Oryx Translational Medicine

PI
Guy Ungerechts, Deputy PI Christoph Springfeld

Trial ID, start of recruitment and status
NCT01387555, 2013, completed & published

Contributing CCU member
Guy Ungerechts, Christoph Springfeld (CCU-associated)

Randomized, open-label phase IIb clinical trial that investigated Pexa-Vec plus best supportive care versus best supportive care in HCC patients who failed sorafenib therapy. Pexa-Vec was given as a single intravenous infusion followed by up to 5 intratumoral injections. Results have been published (see below). In summary, Pexa-Vec was well tolerated and anti-tumor T cell responses were detected. However, no significant differences between treatment arms were observed for overall survival, response rate and time to progression. Induction of immune responses to vaccinia antigens and HCC associated antigens were observed. The results indicate that the treatment of earlier stage patients might be worth exploring.

Publications

• Vaccinia-based oncolytic immunotherapy Pexastimogene Devacirepvec in patients with advanced hepatocellular carcinoma after sorafenib failure: a randomized multicenter Phase IIb trial (TRAVERSE).
  Moehler M, Heo J, Lee HC, Tak WY, Chao Y, Paik SW, Yim HJ, Byun KS, Baron A, Ungerechts G, Jonker D, Ruo L, Cho M, Kaubisch A, Wege H, Merle P, Ebert O, Habersetzer F, Blanc JF, Rosmorduc O, Lencioni R, Patt R, Leen AM, Foerster F, Homerin M, Stojkowitz N, Lusky M, Limacher JM, Hennequi M, Gaspar N, McFadden B, De Silva N, Shen D, Pelusio A, Kirn DH, Breitbach CJ, Burke JM. Oncoimmunology. 2019 Jun 3;8(8):1615817.

Sponsor/Funding
Jennerex Biotherapeutics/Transgene SA

PI
Guy Ungerechts, Deputy PI Christoph Springfeld

Trial ID, start of recruitment and status
NCT02653313, 2015, completed & published

Contributing CCU members
Guy Ungerechts, Barbara Leuchs (CCU-associated), Christine Engeland, Assia Angelova, Jean Rommelaere, Christoph Springfeld (CCU-associated)

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. ParvOryx02 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. This 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 (modified from Hajda et al., BMC Cancer 2017, BioMed Central, under the terms of Creative Commons Attribution 4.0 International License (CC BY 4.0)

Publications

• 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.
  Hajda J, Lehmann M, Krebs O, Kieser M, Geletneky K, Jäger D, Dahm M, Huber B, Schöning T, Sedlaczek O, Stenzinger A, Halama N, Daniel V, Leuchs B, Angelova A, Rommelaere J, Engeland CE, Springfeld C, Ungerechts G. BMC Cancer. 2017 Aug 29;17(1):576.
• Phase 2 Trial of Oncolytic H-1 Parvovirus Therapy Shows Safety and Signs of Immune System Activation in Patients With Metastatic Pancreatic Ductal Adenocarcinoma.
  Hajda J, Leuchs B, Angelova AL, Frehtman V, Rommelaere J, Mertens M, Pilz M, Kieser M, Krebs O, Dahm M, Huber B, Engeland CE, Mavratzas A, Hohmann N, Schreiber J, Jäger D, Halama N, Sedlaczek O, Gaida MM, Daniel V, Springfeld C, Ungerechts G. Clin Cancer Res. 2021 Oct 15;27(20):5546-5556.

Sponsor/Funding
Oryx Translational Medicine

PI
Jessica Hassel, Deputy PI Guy Ungerechts

Trial ID, start of recruitment and status
NCT02366195, 2015, completed

Contributing CCU member
Guy Ungerechts

Aim: Talimogene laherparepvec was administered by intralesional injection into injectable cutaneous, subcutaneous, and nodal lesions at an initial dose of 10⁶ plaque-forming units (PFU) per mL on day 1 followed by a dose of 10⁸ PFU/mL 21 days after the initial dose and every 14 days thereafter. Participants were treated with talimogene laherparepvec until they achieved a complete response, all injectable tumors had disappeared, clinically significant (resulting in clinical deterioration or requiring change of therapy) disease progression beyond 6 months of treatment, per modified World Health Organization (WHO) response criteria, or intolerance of study treatment, whichever occurred first. Primary outcome measure: Correlation Between Baseline Intratumoral CD8+ Cell Density and Objective Response Rate (Time Frame: Intratumoral CD8+ cell density was assessed at Baseline. Response was assessed every 12 weeks until disease progression beyond 6 months of treatment or the start of new anticancer therapy; median time on follow-up was 59 weeks (range 3 - 116 weeks).)
(modified from ClinicalTrials.Gov)

Sponsor / Funding
AMGEN

PI
Guy Ungerechts

Trial ID, start of recruitment and status
NCT02263508, 2016, completed

Contributing CCU member
Guy Ungerechts

Phase 1b Subjects will be treated with talimogene laherparepvec until all injectable tumors have disappeared, disease progression per modified Immune-Related Response Criteria (irRC), or intolerance of study treatment, up to a maximum of 24 months of study treatment. Subjects will be treated with MK-3475 (pembrolizumab) until complete response (CR) disease progression per irRC, or intolerance of study treatment, up to a maximum of 24 months of study treatment. In Phase 3, Subjects will be treated with talimogene laherparepvec plus pembrolizumab(arm 1) or placebo plus pembrolizumab (arm 2) until 24 months from the date of the first dose of pembrolizumab or end of treatment due to disappearance of injectable lesions, complete response, disease progression per irRC-RECIST or intolerance of study treatment. (from ClinicalTrials.gov)

Publications

• A Phase I/III, multicenter, open-label trial of talimogene laherparepvec (T-VEC) in combination with pembrolizumab for the treatment of unresected, stage IIIb-IV melanoma (MASTERKEY-265).
  Long GV, Dummer R, Ribas A, Puzanov I, Michielin O, VanderWalde A, Andtbacka RHI, Cebon J, Fernandez E, Malvehy J, Olszanski AJ, Gajewski TF, Kirkwood JM, Kuznetsova O, Chen L, Kaufman DR, Chou J, Hodi S. J Immunother Cancer. 2015; 3(Suppl 2): P181. Published online 2015 Nov 4.

Sponsor / Funding
Sponsor: Amgen; Collaborator: Merck Sharp & Dohme Corp.

PI
Christoph Springfeld, Deputy PI Guy Ungerechts

Trial ID, start of recruitment and status
NCT02562755, 2017, completed

Contributing CCU members
Christoph Springfeld (associated), Guy Ungerechts

This is an international multi-center randomized Phase 3 study to determine whether treatment with vaccinia virus based immunotherapy (Pexa-Vec) followed by sorafenib increases survival compared to treatment with sorafenib in patients with advanced hepatocellular carcinoma who have not received prior systemic therapy. A total of 600 patients will be randomly assigned to 2 treatment arms in a 1:1 ratio (300 in each arm) to reach at least 570 evaluable patients. (modified from ClinicalTrials.gov)

Sponsor / Funding
Sponsor: SillaJen, Inc

PI
Guy Ungerechts

Trial ID, start of recruitment and status
NCT04521621, 2021, recruiting

Contributing CCU members
Guy Ungerechts, Mathias Leber

This is a phase Ib/II clinical study of intratumoral administration of the oncolytic virus V937 (Coxsackievirus A21) in combination with checkpoint inhibitor pembrolizumab (MK-3475) in patients with advanced/metastatic solid tumors. Safety and dose finding of the above-mentioned combination is a primary objective. Synergistic effects of checkpoint inhibition and oncolytic agent are anticipated

Sponsor / Funding
Merck Sharp & Dohme LLC

PI
Guy Ungerechts

Trial ID, start of recruitment and status
Eudra-CT No: 2020-003996-16, 2022, recruiting

Contributing CCU members
Guy Ungerechts, Mathias Leber

In this study, the hypothesis is that intravenous treatment with oncolytic reovirus pelareorep will prime the tumor microenvironment for checkpoint blockade therapy, thereby increasing PD-L1 expression and the number of new T cell clones within the tumor, both of which are associated with increased response to checkpoint blockade.

Sponsor / Funding
Oncolytics Biotech, Inc.

PI
Guy Ungerechts

Trial ID, start of recruitment
EudraCT-Nr.: 2021-002529-13, Q2/3 2022

Contributing CCU members
Guy Ungerechts, Mathias Leber

The START study is an open-label, non-randomized, first-in-human phase I trial of PeptiCRAd-1 against multiple solid tumors (melanoma, triple-negative breast cancer and NSCLC). This adenovirus-based oncolytic encodes two additional therapeutic transgenes (CD40L, OXO40L), which will be expressed in tumor cells upon infection to further stimulate the innate and adaptive immune response. Moreover, the virus is coated with NY-ESO-1 and MAGE-A3 peptides to direct the immune system against NY-ESO-1 or MAGE-A3-positive tumor cells. Patients will be pre-treated with intravenous cyclophosphamide to enhance the therapeutic efficacy of PeptiCRAd-1, which will be administered intratumorally in six individual doses. PeptiCRAd-1 is combined with immune checkpoint inhibition (pembrolizumab).

Sponsor / Funding
VALO Therapeutics