Phase 1, open-label, dose-escalation study on the safety, pharmacokinetics, and preliminary efficacy of intravenous Coxsackievirus A21 (V937), with or without pembrolizumab, in patients with advanced solid tumors
- PMID: 36669791
- PMCID: PMC9872507
- DOI: 10.1136/jitc-2022-005007
Phase 1, open-label, dose-escalation study on the safety, pharmacokinetics, and preliminary efficacy of intravenous Coxsackievirus A21 (V937), with or without pembrolizumab, in patients with advanced solid tumors
Abstract
Background: Oncolytic virus V937 showed activity and safety with intratumoral administration. This phase 1 study evaluated intravenous V937±pembrolizumab in patients with advanced solid tumors.
Methods: Patients had advanced non-small cell lung cancer (NSCLC), urothelial cancer, metastatic castration-resistant prostate cancer, or melanoma in part A (V937 monotherapy), and metastatic NSCLC or urothelial cancer in part B (V937+pembrolizumab). Prior immunotherapy was permitted >28 days before study treatment. Patients received intravenous V937 on days 1, 3, and 5 (also on day 8 in part B) of the first 21-day cycle and on day 1 of subsequent cycles for eight cycles. Three ascending dose-escalation cohorts were studied. Dose-escalation proceeded if no dose-limiting toxicities (DLTs) occurred in cycle 1 of the previous cohort. In part B, patients also received pembrolizumab 200 mg every 3 weeks from day 8 for 2 years; dose-expansion occurred at the highest-dose cohort. Serial biopsies were performed.
Results: No DLTs occurred in parts A (n=18) or B (n=85). Grade 3-5 treatment-related adverse events (AEs) were not observed in part A and were experienced by 10 (12%) patients in part B. The most frequent treatment-related AEs (any grade) in part B were fatigue (36%), pruritus (18%), myalgia (14%), diarrhea (13%), pyrexia (13%), influenza-like illness (12%), and nausea (12%). At the highest tested dose, median intratumoral V937 concentrations were 117,631 copies/mL on day 8, cycle 1 in part A (n=6) and below the detection limit for most patients (86% (19/22)) on day 15, cycle 1 in part B. Objective response rates were 6% (part A), 9% in the NSCLC dose-expansion cohort (n=43), and 20% in the urothelial cancer dose-expansion cohort (n=35).
Conclusions: Intravenous V937+pembrolizumab had a manageable safety profile. Although V937 was detected in tumor tissue, in NSCLC and urothelial cancer, efficacy was not greater than that observed in previous studies with pembrolizumab monotherapy.
Trial registration number: NCT02043665.
Keywords: Immunotherapy; Lung Neoplasms; Oncolytic Virotherapy; Oncolytic Viruses; Urinary Bladder Neoplasms.
© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Conflict of interest statement
Competing interests: CMR has consulted regarding oncology drug development with AbbVie, Amgen, AstraZeneca, Epizyme, Genentech/Roche, Ipsen, Jazz, Lilly, and Syros. He serves on the scientific advisory boards of Bridge Medicines, Earli, and Harpoon Therapeutics. HSP has received speaker and advisory board honoraria from Ipsen, Eisai, Pfizer, and Bristol Myers Squibb. MZ has received research support (to institution) from Bristol Myers Squibb and Exelixis. He has received advisory board honoraria from Aveo, Exelixis, Janssen, Pfizer, and EMD Serono. WLA is a data safety monitoring board member for Lilly. KJH has received research funding from AstraZeneca, Boehringer-Ingelheim, MSD, and Replimune. He serves on the scientific advisory boards of Arch Oncology, AstraZeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Codiak BioSciences, Inzen Therapeutics, ISA Pharma, Merck-Serono, MSD, Pfizer, and Replimune. He serves on the speaker’s bureau for Bristol Myers Squibb, MSD, and Replimune. DD has received research support (to institution) from Ambrx Biopharma, Beigene, Bristol Myers Squibb, EpimAb, Harbour BioMed, Maxinovel, MSD, Olema Pharmaceuticals, Pfizer, PhamAbcine, Roche, and Haihe Biopharma. She serves on the scientific advisory board of MSD and has received travel support from Novartis. AGH has nothing to disclose. SJO has served on the scientific advisory boards of Biontech, Ultimovacs, Merck, ImaginAB, and Array. He was a consultant for Rad Immune, Bristol Myers Squibb, and Biontech; has served on the speaker’s board for Bristol Myers Squibb; and has received honoraria from Array, Ultimovacs, Merck, Rad Immune, ImaginAB, Biontech, and Bristol Myers Squibb. TDC has received honoraria from AstraZeneca, Merck USA, Novartis, Roche, and Specialized Therapeutics Australia; travel/accommodation support from Astellas; conference support from Novartis; and research support (to institution) from Daiichi Sankyo, Beigene, Janssen, Amgen, Exelixis, Merck, Immutep, and Clovis. He serves on the scientific advisory boards of AstraZeneca, Novartis, and Cipla. GMW has received speaker honoraria from AstraZeneca, Medtronic, Johnson & Johnson, and Device Technologies Australia and consulting fees (Expert Input Forum) from MSD. RRJ has nothing to disclose. DEG has received research funding from AstraZeneca, BerGenBio, and Karyopharm. He serves on the scientific advisory boards of Regeneron, Sanofi, Jansen, Mirati, and Catalyst and on the steering committee of Bristol Myers Squibb. He is a shareholder in Gilead. JER has received research funding (institutional) from Bayer, SeaGen, AstraZeneca, Roche/Genentech, Astellas, and QED Therapeutics. He has received consulting fees from IMVax, Century Tx, Aadi, Alligator, Hengrui, Bayer, SeaGen, AstraZeneca, Roche/Genentech, Astellas, QED Therapeutics, Bristol Myers Squibb, Merck, Pfizer, Pharmacyclics, Boehringer Ingelheim, GlaxoSmithKline, Infinity, Janssen, Mirati, EMD-Serono, Gilead, Lilly, Tyra Biosciences, and Pharmacyclics. He has received honoraria from EMD-Serono, Research to Practice, MJH LifeSciences, Medscape, Uptodate, Clinical Care Options, and OncLive. CR has received research funding (institutional) from Viralytics, Roche, Viralytics/Merck, and Eisai and has participated in a consulting/advisory role with Bristol Myers Squibb. She has received honoraria from Bristol Myers Squibb, Pfizer, Novartis, and Eisai and travel, accommodations, and expenses from Astellas Pharma, Roche, Janssen, GlaxoSmithKline, Bristol Myers Squibb, and Ipsen. DCC has nothing to disclose. BDC has received research funding from Viralytics, Galectin Therapeutics, Clinigen, AstraZeneca (research institution), and Bristol Myers Squibb (research institution). He has participated on the scientific advisory boards of Clinigen, Cullinan Oncology, and Nektar. He is a data safety monitoring board member for Merck USA. JRM has received research funding (institutional) from Sillagen, Vyriad, Replimune, Corvus Pharmaceuticals, Tizona, Trishula Therapeutics, Merck, Eisai, Genentech, Peloton Therapeutics, Seagen, Rubius Therapeutics, and BioNtech. He has participated on the scientific advisory board of Merck. YR is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, USA, and stockholder in Merck & Co., Inc., Rahway, New Jersey, USA. EVS is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, USA, and stockholder in Merck & Co. Inc., Rahway, New Jersey, USA. LG is a former contractor to Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, USA, and stockholder in Merck & Co., Inc., Rahway, New Jersey, USA. SG has received honoraria from SITC advances in Cancer Immunotherapy as the Salt Lake City Program Organizer and presenter, travel support from QED Biopharmaceutical, as well as funding for other clinical trials from Bristol Myers Squibb, Rexahn, Incyte, Novartis, LSK, Five Prime, Mirati, QED, Debiopharm, Merck, Pfizer, AstraZeneca, MedImmune, Clovis, Immunocore, Elevar Therapeutics, and Seattle Genetics.
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