William S. Groene

Phase I Trial of Intravenous Administration of PV701, an Oncolytic Virus, in Patients With Advanced Solid Cancers

PURPOSE PV701, a replication-competent strain of Newcastle disease virus, causes regression of tumor xenografts after intravenous administration. This phase I study was designed to define the maximum-tolerated dose (MTD) and safety of single and multiple intravenous doses of PV701 as a single agent in patients with cancer. PATIENTS AND METHODS Seventy-nine patients with advanced solid cancers that were unresponsive to standard therapy were enrolled. Four PV701 intravenous dosing regimens were evaluated: (1) single dose: one dose every 28 days; (2) repeat dose: three doses in 1 week every 28 days; (3) desensitizing: one lower dose followed by two higher doses in 1 week every 28 days; and (4) two week: one lower dose followed by five higher doses over 2 weeks every 21 days. RESULTS A 100-fold dose intensification was achieved over 195 cycles. A first-dose MTD of 12 x 10(9) plaque-forming units (PFU)/m(2) was established for outpatient dosing. After an initial dose of 12 x 10(9) PFU/m(2), patients tolerated an MTD for subsequent doses of 120 x 10(9) PFU/m(2). The most common adverse events were flu-like symptoms that occurred principally after the first dose and were decreased in number and severity with each subsequent dose. Tumor site-specific adverse events and acute dosing reactions were also observed but not cumulative toxicity. Objective responses occurred at higher dose levels, and progression-free survival ranged from 4 to 31 months. Tumor tissue from one patient was obtained after 11 months of therapy and showed evidence of PV701 particles budding from the tumor cell membrane by electron microscopy and a pronounced lymphoplasmacytic infiltrate by histologic examination. CONCLUSION PV701 warrants further study as a novel therapeutic agent for cancer patients.

Phase 1 Clinical Experience Using Intravenous Administration of PV701, an Oncolytic Newcastle Disease Virus

PV701 is a naturally-attenuated, non-recombinant, oncolytic strain of Newcastle disease virus that displays preclinical intravenous (IV) efficacy. PV701 is selective at killing human cancer cells versus normal human cells based on tumor specific defects in the interferon (IFN)-mediated antiviral response. This oncolytic virus displays a broad spectrum of antitumor activity in vitro and in vivo. Preclinical models successfully predicted key clinical parameters including the mechanism of toxicity, two complementary strategies (desensitization and slow infusion) to reduce toxicity, and the starting dose for phase 1 trials. In three phase 1 trials of 114 patients using IV administration of PV701, Wellstat Biologics Corporation has evaluated the effects of dose, schedule, and infusion rate for PV701. Three general classes of side effects were seen: flu-like symptoms; tumor-site-specific adverse events (AEs); and infusion reactions. The first PV701 dose desensitized the patient to the side effects of further doses, allowing a marked increase in the maximum tolerated dose for subsequent doses compared to the first dose. Tumor responses were first noted at the higher doses achieved using desensitization. In the most recent phase 1 trial of 19 patients at Hamilton, Ontario, that employed desensitization, high repeat doses, and a slower infusion rate (Hamilton Regimen), there were six responses (4 major; 2 minor) and a total of six patients with survival for at least 2 years. In addition, patient tolerability improved using the Hamilton Regimen compared to IV bolus dosing used previously. Phase 2 studies of this novel biologic agent are about to begin.

A Phase 1 Clinical Study of Intravenous Administration of PV701, an Oncolytic Virus, Using Two-Step Desensitization

Purpose: In a previous phase 1 study, adverse events, especially flu-like symptoms, were observed mainly following the first i.v. bolus dose of PV701, an oncolytic Newcastle disease virus. Desensitization to adverse events of subsequent doses occurred, allowing a 10-fold increase in the maximum tolerated dose for these doses. Although one-step desensitization (a single desensitizing dose with higher subsequent doses) addressed the tolerability of high repeat doses, additional testing was required to further improve tolerability of the initial dose. This study tested the hypothesis that two-step desensitization, using two dose increments before high repeat doses, would be well tolerated. Experimental Design: Sixteen adults with incurable solid tumors were enrolled. Cycles consisted of six PV701 doses over 2 weeks followed by a 1-week rest. Doses 1 to 2 were 1 and 12 × 109 plaque-forming units (pfu)/m2, respectively, whereas doses 3 to 6 were escalated by cohort from 24 to 120 × 109 pfu/m2. Results: No dose-limiting toxicities were observed, permitting dose escalation through cohort 4 (1, 12, 120, 120, 120, 120 × 109 pfu/m2). Mild flu-like symptoms were common following the first infusion, diminished with repeated dosing, and were less pronounced than those seen previously. Tumor regression was observed in a patient with anal carcinoma who enrolled with stable disease following palliative radiotherapy. Four patients with clearly progressing cancer before enrollment had disease stabilization of ≥6 months. Conclusions: This novel two-step desensitization improved patient tolerability compared with the previous regimen. Toxicities were predictable and manageable. PV701, the first oncolytic virus to enter phase 1 i.v. testing, continues to show single-agent activity, warranting planned phase 2 trials.

An Optimized Clinical Regimen for the Oncolytic Virus PV701

Purpose: Previous phase 1 trials of i.v.-administered PV701 have shown this virus to be well-tolerated with toxicity primarily associated with the first dose. Our hypothesis, based on preclinical evidence, was that patient tolerability could be improved by slowing the i.v. infusion rate, and that this approach would allow for the safe administration of higher doses. Additionally, this phase 1 trial was the first to measure PV701 clearance. Experimental Design: For the first dose, a 3-h infusion was used compared with the 10- and 30-min infusions administered in the two previous trials. Subsequent doses were infused over 1 h. Six doses were given per 3-week cycle. Escalation of the first dose was done separately from the escalation of doses 2 to 6. Viral clearance was determined using whole blood reverse transcription-PCR. Results: Eighteen patients with advanced chemorefractory cancer were enrolled. The first dose was safely escalated to 24 × 109 plaque-forming units/m2 and doses 2 to 6 were safely escalated to 120 × 109 plaque-forming units/m2. Tolerability was improved compared with the rapid bolus dosing used previously with the elimination of severe flu-like symptoms. Furthermore, infusion reactions were markedly decreased in this trial compared with previous PV701 trials. The presence of neutralizing antibodies did not significantly affect PV701 clearance. Four major and two minor tumor responses were observed. Conclusions: Using slow infusion, patient tolerability was improved, while the first dose was safely escalated relative to two previous PV701 trials. Based on improved tolerability and encouraging signs of activity, this slow infusion regimen was selected for further PV701 clinical development.

Slow intravenous infusion of PV701, an oncolytic virus: Final results of a phase I study

3037 Background: PV701 is a non-recombinant, replication-competent Newcastle disease virus that targets tumor-specific defects in the interferon antiviral response. METHODS In the present phase I study of PV701 in advanced cancer patients (pts), the IV infusion rate of the 1st dose was decreased 18-fold, i.e., administration over 3 hrs compared to the 10 min bolus used previously [JCO 2002, 20:2251]. All other doses were given over 1 hr. A 3 wk cycle included 6 doses/2wks followed by 1wk rest. Dose 1 and doses 2-6 were escalated separately. RESULTS 18 pts (10M:8F) were enrolled and treated for a median of 6 cycles. The 1st dose was escalated from 12 billion plaque forming units (BPFU)/m2 up to the MTD of 24 BPFU/m2 with moderate fever and asymptomatic hypotension noted. Mild-to-moderate flu-like symptoms were the most common adverse events (AEs). These were attributed to elevated levels of plasma cytokines observed and were reduced in severity compared to the previous bolus dosing study. Doses 2-6 were escalated from 24 to 120 BPFU/m2 and were well tolerated. A reduced incidence and severity of AEs occurred with this repeat dosing, even when these doses were 5-fold higher than the first dose, indicating that the desensitization previously observed following bolus dosing was similarly induced following 3-hr infusion. All pts were seronegative at baseline and developed PV701 antibodies by 2 wks post dosing. In the 18 pts, there were 5 responses (PRs: 2 colorectal, 1 melanoma; minor responses: 2 carcinoid) with a median duration of 7 months. 61% of pts (11/18) had a time-to-progression of ≥4 months (range up to 14 months). These results correlate with preclinical findings that slowing the IV infusion rate 20-fold in mice completely abrogated the lethality at the previously determined LD-100, but did not negatively affect response rate. CONCLUSIONS The results of this phase I trial indicate that slow IV infusion of PV701 over 3 hrs was well tolerated and preliminary evidence of efficacy was observed. These observations provide important dosing information for planned Phase II clinical studies and provide an example of the translation of preclinical testing into a successful clinical study. [Table: see text].