PMID- 33875611 OWN - NLM STAT- MEDLINE DCOM- 20211217 LR - 20211217 IS - 2051-1426 (Electronic) IS - 2051-1426 (Linking) VI - 9 IP - 4 DP - 2021 Apr TI - Phase I trial of intratumoral PVSRIPO in patients with unresectable, treatment-refractory melanoma. LID - 10.1136/jitc-2020-002203 [doi] LID - e002203 AB - BACKGROUND: While programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) antagonists have improved the prognosis for many patients with melanoma, around 60% fail therapy. PVSRIPO is a non-neurovirulent rhinovirus:poliovirus chimera that facilitates an antitumor immune response following cell entry via the poliovirus receptor CD155, which is expressed on tumor and antigen-presenting cells. Preclinical studies show that oncolytic virus plus anti-PD-1 therapy leads to a greater antitumor response than either agent alone, warranting clinical investigation. METHODS: An open-label phase I trial of intratumoral PVSRIPO in patients with unresectable melanoma (American Joint Committee on Cancer V.7 stage IIIB, IIIC, or IV) was performed. Eligible patients had disease progression on anti-PD-1 and V-raf murine sarcoma viral oncogene homolog B (BRAF)/mitogen activated protein kinase kinase (MEK) inhibitors (if BRAF mutant). The primary objective was to characterize the safety and tolerability of PVSRIPO. Twelve patients in four cohorts received a total of 1, 2 or 3 injections of PVSRIPO monotherapy, with 21 days between injections. RESULTS: PVSRIPO injections were well tolerated with no serious adverse events (SAEs) or dose-limiting toxicities (DLTs) reported. All adverse events (AEs) were grade (G) 1 or G2 (G1 pruritus most common at 58%); all but two PVSRIPO-treatment related AEs were localized to the injected or adjacent lesions (n=1 G1 hot flash, n=1 G1 fatigue). Four out of 12 patients (33%) achieved an objective response per immune-related response criteria (two observations, 4 weeks apart), including 4/6 (67%) who received three injections. In the four patients with in-transit disease, a pathological complete response (pCR) was observed in two (50%) patients. Following study completion, 11/12 patients (92%) reinitiated immune checkpoint inhibitor-based therapy, and 6/12 patients (50%) remained without progression at a median follow-up time of 18 months. CONCLUSION: Intratumoral PVSRIPO was well tolerated. Despite the limited number of PVSRIPO treatments relative to the overall lesion burden (67% patients>5 lesions), intratumoral PVSRIPO showed promising antitumor activity, with pCR in injected as well as non-injected lesions in select patients. TRIAL REGISTRATION NUMBER: NCT03712358. CI - (c) Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. FAU - Beasley, Georgia M AU - Beasley GM AUID- ORCID: 0000-0001-6387-9030 AD - Department of Surgery, Duke University, Durham, North Carolina, USA georgia.beasley@duke.edu. AD - Duke Cancer Institute, Duke University, Durham, NC, USA. FAU - Nair, Smita K AU - Nair SK AD - Department of Surgery, Duke University, Durham, North Carolina, USA. AD - Duke Cancer Institute, Duke University, Durham, NC, USA. AD - Department of Pathology, Duke University, Durham, North Carolina, USA. AD - Department of Neurosurgery, Duke University, Durham, NC, USA. FAU - Farrow, Norma E AU - Farrow NE AD - Department of Surgery, Duke University, Durham, North Carolina, USA. FAU - Landa, Karenia AU - Landa K AD - Department of Surgery, Duke University, Durham, North Carolina, USA. FAU - Selim, Maria Angelica AU - Selim MA AD - Department of Pathology, Duke University, Durham, North Carolina, USA. FAU - Wiggs, Carol Ann AU - Wiggs CA AD - Duke Cancer Institute, Duke University, Durham, NC, USA. FAU - Jung, Sin-Ho AU - Jung SH AD - Duke Cancer Institute, Duke University, Durham, NC, USA. AD - Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA. FAU - Bigner, Darell D AU - Bigner DD AD - Duke Cancer Institute, Duke University, Durham, NC, USA. AD - Department of Pathology, Duke University, Durham, North Carolina, USA. AD - Department of Neurosurgery, Duke University, Durham, NC, USA. FAU - True Kelly, Andrea AU - True Kelly A AD - Istari Oncology Inc, Morrisville, North Carolina, USA. FAU - Gromeier, Matthias AU - Gromeier M AD - Duke Cancer Institute, Duke University, Durham, NC, USA. AD - Department of Neurosurgery, Duke University, Durham, NC, USA. AD - Department of Molecular Genetics and Biology, Duke University, Durham, NC, USA. AD - Department of Medicine, Duke Univeristy, Durham, NC, USA. FAU - Salama, April Ks AU - Salama AK AD - Duke Cancer Institute, Duke University, Durham, NC, USA. AD - Department of Medicine, Duke Univeristy, Durham, NC, USA. LA - eng SI - ClinicalTrials.gov/NCT03712358 GR - R35 CA197264/CA/NCI NIH HHS/United States GR - T32 CA093245/CA/NCI NIH HHS/United States GR - P30 CA021765/CA/NCI NIH HHS/United States GR - P30 CA014236/CA/NCI NIH HHS/United States GR - K08 CA237726/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - England TA - J Immunother Cancer JT - Journal for immunotherapy of cancer JID - 101620585 SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Female MH - Humans MH - Male MH - Melanoma/immunology/*therapy MH - Middle Aged MH - North Carolina MH - *Oncolytic Virotherapy/adverse effects MH - Oncolytic Viruses/immunology/*pathogenicity MH - Poliovirus/immunology/*pathogenicity MH - Rhinovirus/immunology/*pathogenicity MH - Skin Neoplasms/immunology/*therapy/virology MH - Time Factors MH - Treatment Outcome PMC - PMC8057552 OTO - NOTNLM OT - melanoma OT - oncolytic virotherapy COIS- Competing interests: SKN owns intellectual property related to this research, which has been licensed to Istari Oncology, Inc. DDB and MG have financial interest in Istari Oncology, Inc. Duke University (Licensor of PVSRIPO) has a financial interest in Istari Oncology, Inc. EDAT- 2021/04/21 06:00 MHDA- 2021/12/18 06:00 PMCR- 2021/04/19 CRDT- 2021/04/20 05:54 PHST- 2021/03/14 00:00 [accepted] PHST- 2021/04/20 05:54 [entrez] PHST- 2021/04/21 06:00 [pubmed] PHST- 2021/12/18 06:00 [medline] PHST- 2021/04/19 00:00 [pmc-release] AID - jitc-2020-002203 [pii] AID - 10.1136/jitc-2020-002203 [doi] PST - ppublish SO - J Immunother Cancer. 2021 Apr;9(4):e002203. doi: 10.1136/jitc-2020-002203.