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 × 10 9 plaque-forming units (pfu)/m 2 , respectively, whereas doses 3 to 6 were escalated by cohort from 24 to 120 × 10 9 pfu/m 2 .
Results: No dose-limiting toxicities were observed, permitting dose escalation through cohort 4 (1, 12, 120, 120, 120, 120 × 10 9 pfu/m 2 ). 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.
Uridine triacetate has been shown to be an effective antidote against mortality and toxicity caused by either overdoses or exaggerated susceptibility to the widely used anticancer agents ...5-fluorouracil (5-FU) and capecitabine. However, a direct assessment of efficacy based on when emergency treatment was initiated was not clinically feasible. In this study we used mouse models of 5-FU overdose and of dihydropyrimidine dehydrogenase (DPD) deficiency to compare the efficacy of uridine triacetate in reducing toxicity and mortality when treatment was initiated at time points from 4 to 144 h after administration of 5-FU. We found that uridine triacetate was effective both in the 5-FU overdose and DPD deficiency models. Starting treatment within 24 h was most effective at reducing toxicity and mortality in both models, while treatment starting more than 96 to 120 h after 5-FU was far less effective. Uridine triacetate also reduced mortality in the DPD deficiency model when mice were treated with the 5-FU prodrug capecitabine. The results of this study are supportive of clinical observations and practice, indicating that efficacy declined progressively with later and later treatment initiation. Prompt treatment with uridine triacetate, within 24 h, conferred the greatest protection against 5-FU overexposure.
•Uridine triacetate reduced mortality from 5FU overdose and DPD deficiency.•Treatment within 24 h conferred the greatest protection against 5FU overexposure.•Delaying uridine triacetate administration led to greater toxicity and mortality.•Little benefit was observed when uridine triacetate was given 96–120 h after 5FU.•Results support clinical evidence of reduced 5FU/capecitabine mortality and toxicity.
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.
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 × 10 9 plaque-forming units/m 2 and doses 2 to 6 were safely escalated to 120 × 10 9 plaque-forming units/m 2 . 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.
Abstract only
e20592
Background: 5-Fluorouracil (5-FU) is broadly used to treat solid tumors. It is typically administered by IV infusion, at or near its maximum tolerated dose, over several days. ...The use of infusion pumps increases the possibility of life-threatening or lethal toxicity due to errors in pump programming, infusion reservoir errors and dosage miscalculations. Partial or total dihydropyrimidine dehydrogenase (DPD) deficiency, which predisposes patients (up to 3% of the population) to impaired 5-FU elimination, can also result in serious or lethal toxicity, Uridine triacetate is an orally bioavailable direct biochemical antagonist of 5-FU toxicity that has been used successfully to treat patients in emergency overdose situations as well as patients with known or suspected overexposure to 5-FU due to DPD deficiency or other causes. Approximately 100 patients at excess risk of 5-FU toxicity due to 5-FU overdose, accidental Xeloda (capecitabine) ingestion, or possible DPD deficiency (rapid onset of severe toxicities) have been treated with uridine triacetate using a common treatment regimen and protocol. More than 80 of these cases have occurred since uridine triacetate data were presented at ASCO in 2009. Methods: Uridine triacetate was provided under emergency IND provisions or an expanded access protocol when requested by qualified clinical sites following 5-FU overexposures, most due to infusion pump errors. Patients received uridine triacetate (10g q6h for 20 doses) as soon as possible after recognition of the overdose or possible clearance defect. Clinical outcomes, including safety and resumption of chemotherapy, were monitored. Results: To date, 98 patients overexposed to 5-FU have been treated with uridine triacetate. 96 of these 98 patients recovered fully. Reductions in or absence of GI, hematologic, and other toxicities associated with 5-FU poisoning were observed. Adverse events attributable to urdine triacetate were infrequent and mild in severity. Conclusions: Uridine triacetate appears to be a safe and effective life-saving antidote for 5-FU overexposure in emergency situations.
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