First-in-man phase I trial of two schedules of the novel synthetic tetrahydroisoquinoline alkaloid PM00104 (Zalypsis) in patients with advanced solid tumours

Abstract

Background:PM00104 binds guanines at DNA minor grooves, impacting DNA replication and transcription. A phase I study was undertaken to investigate safety, dose-limiting toxicities (DLTs), recommended phase II dose (RP2D), pharmacokinetics (PKs) and preliminary antitumour activity of PM00104 as a 1- or 3-h infusion three-weekly.Methods:Patients with advanced solid tumours received PM00104 in a dose escalation trial, as guided by toxicity and PK data.Results:A total of 47 patients were treated; 27 patients on the 1-h schedule (0.23–3.6 mg m−2) and 20 patients on the 3-h schedule (1.8–3.5 mg m−2). Dose-limiting toxicities comprised reversible nausea, vomiting, fatigue, elevated transaminases and thrombocytopenia, establishing the 1-h schedule RP2D at 3.0 mg m−2. With the 3-h schedule, DLTs of reversible hypotension and neutropenia established the RP2D at 2.8 mg m−2. Common PM00104-related adverse events at the RP2D comprised grade 1–2 nausea, fatigue and myelosuppression. In both schedules, PKs increased linearly, but doses over the 1-h schedule RP2D resulted in higher than proportional increases in exposure. A patient with advanced urothelial carcinoma had RECIST shrinkage by 49%, and three patients had RECIST stable disease ⩾6 months.Conclusion:PM00104 is well tolerated, with preliminary evidence of antitumour activity observed. The 1-h 3-weekly schedule is being assessed in phase II clinical trials.

Comparison ofin vitroandin vivobiological effects of trabectedin, lurbinectedin (PM01183) and Zalypsis® (PM00104)

“…Although it contains the same pentacyclic skeleton of trabectedin, it lacks the 10‐member lactone bridge and the additional tetrahydroisoquinoline that is replaced by a trifluorocinammic acid moiety. As previously reported, this compound shows a good antitumor activity both in vitro and in vivo in solid and hematological tumors, and is under clinical evaluation in a phase II trial in multiple myeloma …”

“…At the clinical level, the pharmacokinetic properties of the three compounds appear to be different. The important structural differences of Zalypsis® could justify its differential pharmacokinetic compared with the other two compounds . What was instead surprising is that trabectedin and lurbinectedin, which are structurally very similar, show important differences in their pharmacokinetics .…”

“…The important structural differences of ZalypsisV R could justify its differential pharmacokinetic compared with the other two compounds. 23 What was instead surprising is that trabectedin and lurbinectedin, which are structurally very similar, show important differences in their pharmacokinetics. 19 For example, the volume of distribution of trabectedin and lurbinectedin are respectively 2000 L 41 and 478 L. 19 Interesting to note that in mice the Maximum Tolerated Dose (MTD) of trabectedin was only slightly lower than that of lurbinectedin; around 1.5 and 5 mg/m 2 respectively in humans, 19 suggesting that the differences observed in humans might be even greater than those found in mice.…”

“…As previously reported, 21,22 this compound shows a good antitumor activity both in vitro and in vivo in solid and hematological tumors, and is under clinical evaluation in a phase II trial in multiple myeloma. 23,24 The aim of this study was to compare the pattern of sensitivity of different tumor cell lines with specific DNA repair defects to the three compounds and to assess their in vivo activity in syngenic and xenograft mice models.…”

Finding chemo: the search for marine-based pharmaceutical drugs active against cancer

“…One study evaluated the safety, tolerability and DLTs of zalypsis. [143] A total of 47 patients with advanced solid tumours were enrolled in this study, where two groups consisting of 27 and 20 patients were intravenously administered with zalypsis at a starting dose of 0.23 mg/m 2 at 1-h infusions thrice-weekly and 1.8 mg/m 2 at 3-h infusions thrice-weekly, respectively. At the conclusion of the study, a dose of 3.0 mg/m 2 on a 1-h schedule and 2.8 mg/m 2 on a 3-h schedule were recommended for future use.…”