6 research outputs found
Recommended from our members
505 Relationship of infusion duration and dose to safety, efficacy and pharmacodynamics: second part of a phase 1–2 study using VSV-IFNβ-NIS (VV1) oncolytic virus in patients with refractory solid tumors
BackgroundOncolytic viruses (OVs) show significant potential for treating tumors alongside immunotherapies.1 VV1 is an OV derived from the innocuous vesicular stomatitis virus (VSV). VV1 has been engineered to expresses human interferon (IFN) β and thyroidal sodium iodide symporter (NIS).2 VV1-infected cells produce IFNβ, which protects non-cancer cells from VV1 and allows VV1 to spread more efficiently in cancerous tissue.3 4 NIS expression on cells imports 99mTc pertechnetate, which facilitates in vivo imaging of virus infection.2 This three-part, phase 1–2 study was designed to determine the safety and tolerability of VV1 in patients with advanced unresectable and metastatic solid tumors. Here we report on the second part of this study: selection of recommended phase 2 regimen (RP2D), comprising further assessment of both duration and dose.MethodsPatients (n=29) were enrolled to receive a single IV infusion of VVI monotherapy. 23 patients received IV VV1 1.7 x1010 TCID50 over 15, 30, 60 or 180 min. Six patients received 1.0 x1011 TCID50 over 30 min with aggressive premedication and fluid support overnight. Patients were monitored for dose limiting toxicities over 21 days with efficacy assessments after 6 weeks and then every 3 months for survival. The primary objective was to establish the safety and tolerability of IV VV1. Secondary objectives included preliminary efficacy, pharmacokinetics and pharmacodynamics.ResultsIn this study VV1, demonstrated an acceptable safety profile. No deaths or Grade 4 infusion-related reactions (IRR) were reported. VV1 shedding by buccal swabs was negative at all study visits. Peak IFNβ serum levels and preliminary efficacy signals (2 PRs) were associated with 30 min infusion duration and higher dose, with RECIST data pending for 1 x 1011(table 1).Abstract 505 Table 1ConclusionsIn this study, the absence of viral shedding demonstrates that VV1 is safe for patient and caregiver with little/no environmental impact. There was no difference in safety between the lower and the higher dose infusions. In this patient population acceptable tolerability was observed at the higher dose with 30 min duration, thus the RP2D is 1x 1011 over 30 mins.Trial RegistrationNCT02923466ReferencesHemminki O, Dos Santos JM, Hemminki A. Oncolytic viruses for cancer immunotherapy. J Hematol Oncol 2020;13(1):84.Naik S, Nace R, Federspiel MJ, Barber GN, Peng KW, Russell SJ. Curative one-shot systemic virotherapy in murine myeloma. Leukemia 2012;26(8):1870–1878.Barber GN. Vesicular stomatitis virus as an oncolytic vector. Viral Immunol 2004;17(4):516–527.Lichty BD, Power AT, Stojdl DF, Bell JC. Vesicular stomatitis virus: re-inventing the bullet. Trends Mol Med 2004;10(5):210–216.Ethics ApprovalEthics approval was granted by WCG IRB. IRB tracking number: 20163005. Voluntary written informed consent was obtained from every patient prior to participation
Recommended from our members
Relationship of infusion duration to safety, efficacy, and pharmacodynamics (PD): Second part of a phase I-II study using VSV-IFNβ-NIS (VV1) oncolytic virus in patients with refractory solid tumors
3090 Background: VV1 (Voyager V1) is derived from VSV, an RNA virus with low human seroprevalence, engineered to replicate selectively in and kill human cancer cells. In Part 1 of this study, we demonstrated the safety of intratumoral VV1 and dose-response, using serum IFNβ as a biomarker; we observed viral replication in tumor and concomitant lymphocyte/neutrophil trafficking (SITC 2018). 2 other studies suggested greater efficacy and higher IFNβ levels with IV administration. Longer infusion durations were reported to mitigate infusion reactions (IRRs) for another oncolytic. Methods: We studied 3 different infusion durations of VV1 monotherapy at the recommended phase 2 IV dose (1.7 x 1010 TCID50) in patients with advanced solid tumors. Endpoints included safety, preliminary anti-tumor activity, viral titers, IFNβ PD and shedding. Patients received IV VV1 once on D1 and were monitored for DLT over 21 days with efficacy assessments every 6 weeks. IRRs were classified using Lee 2014 criteria for CRS as either constitutional symptoms only (G1) or involving hypotension (G2). Results: 18 patients were treated at 30, 60 and 180-minute durations (n = 7, 5 and 6, respectively). No DLTs, deaths or G3-4 related IRR AEs were observed. Most pts were female (67%), white (100%), with ECOG PS 0 (61%) and median 4 lines of prior systemic therapy (range 1-14) for colorectal (CRC; 56%), squamous cell carcinoma (11%), pheochromocytoma (11%), sarcoma (11%) or other (11%) cancers. The table shows results (number of patients) by infusion duration. Conclusions: There was no difference in safety between the 3 infusion durations, while efficacy and PD markers suggested better anti-tumor effect with 30-minute infusion. VV1 is safe for caregivers, with no viral shedding. Part 3 of this study will now treat CRC patients with VV1 in combination with a checkpoint inhibitor (avelumab). A 5-arm phase 2 basket study in combination with cemiplimab is proceeding with 30-minute infusions. Clinical trial information: NCT02923466 . [Table: see text
Recommended from our members
422 Safety and efficacy of neoadjuvant intravesical oncolytic MV-NIS in patients with urothelial carcinoma
BackgroundBladder cancer is a leading cause of cancer death in the United States.1 The histology in > 90% of cases is urothelial carcinoma (UC). Tumors may present either as non-muscle-invasive (NMIBC) or muscle-invasive disease (MIBC). Current standard of care for patients with high risk NMIBC includes transurethral resection of bladder tumor (TURBT) followed by intravesical immunotherapy with Bacillus Calmette-Guerin (BCG).2 Meanwhile, patients with BCG unresponsive NMIBC or MIBC are recommended to undergo radical cystectomy (RC), which adversely impacts quality of life and is associated with significant morbidity.3 MV-NIS is an investigational oncolytic measles virus with an excellent clinical safety profile.4 This ongoing phase I clinical study is designed to test the safety, efficacy and identify the recommended phase 2 dose (RP2D) of intravesical MV-NIS in patients with NMIBC or MIBC who are scheduled for RC and not eligible for neoadjuvant chemotherapy.MethodsBladder UC patients were evaluated for eligibility and provided informed consent prior to enrolling. To date 8 patients have been enrolled: 4 to the single dose safety cohort, and 4 to the multi-dose expansion cohort. Patients were administered intravesical ~1x109 TCID50 MV-NIS once at least 1 week prior to RC (safety cohort), or twice at 4 and 2 weeks prior to RC (expansion cohort). Patients were closely monitored during the 2-hour instillation period. Tumor specimens from the pre-treatment TURBT and post-treatment RC were analyzed to determine pre- and post-treatment pathological stage and evaluate tumor killing and immune cell infiltrate.ResultsIntravesical MV-NIS treatment was well tolerated in all patients. Only a single Adverse Event (AE) attributable to MV-NIS treatment (Grade 1 hematuria). AEs Grade>2 were related to post-surgical complications. Tumor pathology findings are summarized in table 1. Tumor downstaging was observed in 4 of 8 patients. Among 4 patients in the expansion cohort, 2 had no residual disease (pT0). Central assessment of RC tissues showed significant inflammatory infiltrate in all treated bladder specimens. Detailed analyses are ongoing to characterize MV infection and immune infiltrate in bladder tissueAbstract 422 Table 1Pre-treatment (TURBT) and post- treatment (RC) pathologyConclusionsThe higher-than-expected rate of tumor downstaging and pT0 pathology, paired with the significant immune infiltrate observed in post-treatment bladder tissue, provide compelling evidence that intravesical MV-NIS has clinical activity against UC. These results support the use of two doses of ~1x109 TCID50 as the RP2D in future clinical studies for BCG unresponsive NMIBC or MIBC patients. MV-NIS induced inflammation may act synergistically with checkpoint blockade therapies.Trial RegistrationNCT03171493ReferencesSiegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin 2019;69(1):7–34.Knowles MA, Hurst CD. Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nat Rev Cancer 2015;15(1):25–41.Zakaria AS, Santos F, Dragomir A, Tanguay S, Kassouf W, Aprikian AG. Postoperative mortality and complications after radical cystectomy for bladder cancer in Quebec: A population-based analysis during the years 2000–2009. Can Urol Assoc J 2014;8(7–8):259–267.Galanis E, Atherton PJ, Maurer MJ, Knutson KL, Dowdy SC, Cliby WA, Haluska P Jr, Long HJ, Oberg A, Aderca I, Block MS, Bakkum-Gamez J, Federspiel MJ, Russell SJ, Kalli KR, Keeney G, Peng KW, Hartmann LC. Oncolytic measles virus expressing the sodium iodide symporter to treat drug-resistant ovarian cancer. Cancer Res 2015;75(1):22–30.Ethics ApprovalApproval was received from the Institutional Review boards (IRBs) at all clinical sites including Mayo Clinic (#17–004167); Ochsner Health (#2020 060); and University of Miami (#20200174). All study participants are required to review and sign an IRB approved informed consent before taking part in the clinical trial
Phase 1 dose escalation, food effect, and biomarker study of RG7388, a more potent second-generation MDM2 antagonist, in patients (pts) with solid tumors.
Recommended from our members
Safety and efficacy of neoadjuvant intravesical oncolytic MV-NIS in patients undergoing radical cystectomy (RC) for urothelial carcinoma but ineligible for neoadjuvant cisplatin-based chemotherapy
TPS3172
Background: Bladder cancer is a leading cause of cancer death in the United States. Over 90% of bladder cancer cases are urothelial carcinomas (UC) that may present as a non-muscle-invasive (NMIBC) or muscle-invasive disease (MIBC). Standard of care for NMIBC includes transurethral resection of bladder tumor (TURBT), intravesical chemotherapy and immunotherapy with Bacillus Calmette-Guerin (BCG). Patients (pts) with high-grade BCG-refractory NMIBC or MIBC undergo RC, which involves complete bladder removal and pelvic lymphadenectomy. RC severely impacts quality of life with significant morbidity. Oncolytic viruses are showing promise in UC, and MV-NIS has proven efficacy in other tumor types. MV-NIS is an investigational oncolytic measles virus with an excellent safety profile, irrespective of route of administration (n > 100). MV-NIS-related adverse events are limited to infusion reactions and transient CBC changes, and little local toxicity is anticipated with intravesical therapy. Clinical efficacy of this oncolytic may be related to absence of measles immunity. Based on this, the clinical strategy for MV-NIS is focused on targeting immune-privileged sites via intra-tumoral or intravesical routes, alone or in combination with checkpoint inhibitors. We hypothesize that intravesical therapy with oncolytic MV-NIS can improve clinical outcomes for (a) BCG refractory NMIBC pts to avoid or delay the need for RC; and (b) MIBC pts undergoing RC. Methods: This study is enrolling pts undergoing RC who are ineligible to receive neoadjuvant chemotherapy. The trial has 2 stages to (a) determine the safety and tolerability of intravesical MV-NIS, and (b) assess preliminary efficacy. Part (a) includes 4-24 pts in a timing cohort with doses administered at increasing durations (1-4 weeks) prior to RC to establish safety of a single MV-NIS dose. Part (b) includes an expansion cohort (n = 12) to evaluate the safety and efficacy of 2 intravesical doses of MV-NIS at 2-week intervals prior to RC. Safety is assessed using NCI-CTCAE V5 and Clavien-Dindo grading of operative complications. The efficacy endpoint is pathologic stage at time of RC (pT0 rate), which can be compared to pre-study TURBT stage. Additional exploratory studies include PK and PD analyses in urine, blood and tumor. Enrollment is ongoing at 2 Mayo Clinic sites (Rochester, MN and Jacksonville, FL) and the study has now progressed from the timing cohort into the expansion cohort. Clinical trial information: NCT03171493