Phase I, multicenter, open-label study of intravenous VCN-01 oncolytic adenovirus with or without nab-paclitaxel plus gemcitabine in patients with advanced solid tumors

Abstract

Background: VCN-01 is an oncolytic adenovirus (Ad5 based) designed to replicate in cancer cells with dysfunctional RB1 pathway, express hyaluronidase to enhance virus intratumoral spread and facilitate chemotherapy and immune cells extravasation into the tumor. This phase I clinical trial was aimed to find the maximum tolerated dose/recommended phase II dose (RP2D) and dose-limiting toxicity (DLT) of the intravenous delivery of the replication-competent VCN-01 adenovirus in patients with advanced cancer.

Methods: Part I: patients with advanced refractory solid tumors received one single dose of VCN-01. Parts II and III: patients with pancreatic adenocarcinoma received VCN-01 (only in cycle 1) and nab-paclitaxel plus gemcitabine (VCN-concurrent on day 1 in Part II, and 7 days before chemotherapy in Part III). Patients were required to have anti-Ad5 neutralizing antibody (NAbs) titers lower than 1/350 dilution. Pharmacokinetic and pharmacodynamic analyses were performed.

Results: 26% of the patients initially screened were excluded based on high NAbs levels. Sixteen and 12 patients were enrolled in Part I and II, respectively: RP2D were 1×10¹³ viral particles (vp)/patient (Part I), and 3.3×10¹² vp/patient (Part II). Fourteen patients were included in Part III: there were no DLTs and the RP2D was 1×10¹³ vp/patient. Observed DLTs were grade 4 aspartate aminotransferase increase in one patient (Part I, 1×10¹³ vp), grade 4 febrile neutropenia in one patient and grade 5 thrombocytopenia plus enterocolitis in another patient (Part II, 1×10¹³ vp). In patients with pancreatic adenocarcinoma overall response rate were 50% (Part II) and 50% (Part III). VCN-01 viral genomes were detected in tumor tissue in five out of six biopsies (day 8). A second viral plasmatic peak and increased hyaluronidase serum levels suggested replication after intravenous injection in all patients. Increased levels of immune biomarkers (interferon-γ, soluble lymphocyte activation gene-3, interleukin (IL)-6, IL-10) were found after VCN-01 administration.

Conclusions: Treatment with VCN-01 is feasible and has an acceptable safety. Encouraging biological and clinical activity was observed when administered in combination with nab-paclitaxel plus gemcitabine to patients with pancreatic adenocarcinoma.

Trial registration number: NCT02045602.

Keywords: clinical trials as topic; gastrointestinal neoplasms; oncolytic virotherapy; tumor microenvironment.

Figure 1

Pharmacokinetics and pharmacodynamics. (A) Pharmacokinetics. None of the patients treated at dose 1×10¹¹ vp, and two out of four patients at dose 1×10¹² vp showed VCN-01 genomes detected in blood from day 3 to 28. By contrast, most of the patients treated at the highest dose levels (3.3×10¹² and 1×10¹³ vp) experienced secondary viremia peaks from 24 hours onwards and maintained VCN-01 genomes in blood for over 3 weeks after its administration. (B) Viral genome load in tumor biopsies. On day 8, the presence of VCN-01 was demonstrated in five out of six subjects (three out of four subjects in the 3×10¹² vp level and both subjects in the 1×10¹³ vp level). One biopsy obtained from a lymph node metastasis in patient with pancreatic cancer 8 days after being dosed with VCN-01 at 3×10¹² vp showed detectable expression of viral proteins in tumor cell nuclei. Positive staining was located adjacent to necrotic areas in the tumor biopsy. (C) Immunohistochemistry of E1A staining for viral replication colocalized with CD8 +in the tumor. VCN-01 also induced a potent inflammatory response, as evidenced by IDO upregulation within the same infected area (interferon- γ target). IDO, indoleamine 2,3-dioxygenase; vp, viral particles.

Figure 2

PH20 expression and detection in serum. PH20 expression from VCN-01 was measured on serum by ELISA in treated patients at different time points. PH20 expression in serum samples at different time points is expressed as pg/mL minus background levels detected for each sample at day 0 and represented in box and Whiskers graphs. An increase in hyaluronidase serum levels was detected in all 33 analyzed patients. One-way analysis of variance Dunnett’s multiple comparisons test was statistically significant of the different time points (*p<0.05 vs D0). vp, viral particles.

Figure 3

Antitumor effects of VCN-01. (A) Part II. Change in tumor burden in patients receiving concurrent VCN-01 and nab-paclitaxel plus gemcitabine. (B) Part III. Change in tumor burden in patients receiving delayed VCN-01 and nab-paclitaxel plus gemcitabine. (C) Waterfall plot of tumor burden changes in patients included in Parts II and III of the study. (D) Maximum change in tumor size (%) versus tumor diameter at start of treatment showed no association between starting tumor size with antitumor efficacy. CR, complete response; ORR, overall response rate; PR, partial response; SD, stable disease; vp, viral particles.