Intravascular adenoviral agents in cancer patients: lessons from clinical trials

Abstract

A large number of adenoviral agents are being developed for the treatment of cancer. However, the treatment-related death of a patient with ornithine transcarbamylase deficiency following adenovirus administration by hepatic artery has led to serious concerns regarding the safety of intravascular adenovirus. Both replication-incompetent (rAd.p53, e.g., SCH58500) and replication-selective (dl1520, aka Onyx-015; CG7870) oncolytic adenoviruses, by intravascular administration, are in clinical trials. We review Phases I and I/II results from these clinical trials. dl1520 and rAd.p53 were well-tolerated following hepatic artery infusion at doses of up to 2x10(12) and 2.5x10(13) particles, respectively. At a dose of 7.5x10(13) particles, rAd.p53 was associated with dose-limiting cardiac output suppression; dl1520 dose escalation did not proceed higher than 2x10(12). Intravenous (i.v.) infusions of dl1520 and CG7870 have been well tolerated by i.v. infusion at doses of 2x10(13) and 6x10(12), respectively, without identification of a maximally tolerated dose to date. Mild/moderate transaminitis was demonstrated in some patients on both the hepatic arterial and i.v. trials at doses >or=10(12) particles. Interleukin (IL)-6 and IL-10 were induced in a dose-dependent manner in most patients, but significant interpatient and intrapatient (on repeat doses) variabilities were demonstrated. Evidence of p53 gene expression (Ad.p53) or viral replication (dl1520) was demonstrated in the majority of patients receiving >or=10(12) particles. Over 100 cancer patients have been treated with intravascular adenovirus constructs to date with an acceptable toxicity profile; further clinical trial testing appears appropriate in cancer patients.

Figure 1

Pharmacokinetics of Onyx-015 following h.a.i. The first five patients treated at the 2×10¹² particles dose level had pharmacokinetic blood draws taken on cycle 1 (day 1) at the following timepoints after infusion: 5, 10, 30, 60, 90, 120, 180, and 360 minutes. Plasma was tested for virus by quantitative PCR.

Figure 2

Laboratory changes versus dose following h.a.i. of SCH58500 rAd.p53. The maximum nadir following treatment was determined and related to baseline values for blood counts (Panel A) and transaminases (Panel B). Blood counts generally dropped within 72 hours and transaminases increased within 5 days. Laboratory abnormalities generally returned to normal within 10 days.

Figure 3

Evidence for viral replication and shedding into the blood. Quantitative PCR of the blood for detection of Onyx-015 was performed on this patient daily posttreatment. Since Onyx-015 was cleared from the blood within the first 6 hours after infusion, the presence of virus at later timepoints was indicative of ongoing viral replication and shedding into the blood.

Figure 4

Evidence for viral infection in cancer patients: correlation with viral dose. Onyx-015 replication postinfection was measured on day 4 indirectly as described in the legend (Panel A). SCH58500 rAd.p53 gene expression was measured using RT-PCR on biopsies obtained at laparotomy 2–7 days post-HAI (Panel B). The dose at which biological activity was reproducibly seen was similar in the two trials.