Phase I safety, pharmacokinetic, and pharmacogenomic trial of ES-285, a novel marine cytotoxic agent, administered to adult patients with advanced solid tumors

Abstract

A dose-escalation, phase I study evaluated the safety, pharmacokinetics, pharmacogenomics, and efficacy of ES-285, a novel agent isolated from a marine mollusc, in adult cancer patients. Patients received a 24-hour i.v. infusion of ES-285 once every 3 weeks until disease progression or unacceptable toxicity. The starting dose was 4 mg/m 2 . Dose escalation in cohorts of at least three patients proceeded according to the worst toxicity observed in the previous cohort. Twenty-eight patients were treated with 72 courses of ES-285 across eight dose levels. No dose-limiting toxicities were seen between 4 and 128 mg/m 2 . Two of four patients treated at 256 mg/m 2 had dose-limiting reversible grade 3 transaminitis; one patient at 256 mg/m 2 also had transient grade 3 central neurotoxicity. One of three patients subsequently treated at 200 mg/m 2 died following drug-related central neurotoxicity. Other toxicities included phlebitis, nausea, fatigue, and fever. Pharmacokinetic studies indicated dose proportionality with high volume of distribution (median V ss at 256 mg/m 2 was 2,389 liters; range, 1,615-4,051 liters) and long elimination half life (median t 1/2 at 256 m g / m 2 was 28 h; range, 21-3 2 h ) . T h e t h r e e patients with dose-limiting toxicity had the highest drug exposure. Pharmacogenomic studies of paired surrogate tissue samples identified changes in gene expression following treatment that correlated with increasing dose. Disease stabilization for 6 to 18 weeks was recorded in nine patients. Using this schedule, 128 mg/m 2 was considered safe and feasible. At this dose, pharmacologically relevant concentrations of the drug were safely achieved with pharmacogenomic studies indicating changes in the expression of genes of potential mechanistic relevance.

Spisulosine (ES-285) given as a weekly three-hour intravenous infusion: results of a phase I dose-escalating study in patients with advanced solid malignancies

“…Of note, three patients had grade 3 AST increases, and 2 patients had grade 3 ALT increases, one of these adverse drug reactions qualifying as the only DLT observed in this trial. These safety findings are consistent with preclinical investigations and other early clinical studies [6][7][8][9], with reversible transaminase increases reported at the highest doses in concurrent phase I clinical trials with Spisulosine using 3 and 24-h i.v. infusions every 3 weeks.…”

“…One patient treated with Spisulosine 200 mg/m 2 as a 24-h i.v. infusion developed grade 3 drugrelated central neurotoxicity, which led to the patient's death 6 days after the first administration of the experimental agent [6]. The neurotoxic potential of the drug was confirmed in our study.…”

“…At that time, only short-lasting stable disease had been reported as efficacy signal from these trials. The seriousness of the neurological toxicity experienced by one patient [6] supported this decision.…”

“…Spisulosine, a compound of marine origin, which has antitumor activity in preclinical models [1,6], was studied as a weekly 3-h i.v. infusion in doses ranging from 4 to 200 mg/m 2 .…”

“…Spisulosine seems also to be capable of activating caspases 3 and 12, the poly ADP-ribose polymerase pathway, and p53 phosphorylation [5]. Four different administration schemes of single-agent Spisolusine have been assessed in separate clinical phase I studies [6][7][8][9]. The current trial evaluated a 3-h infusion given i.v.…”