A phase I and pharmacokinetic study of elisidepsin (PM02734) in patients with advanced solid tumors.

PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and recommended phase II dose (RD) of elisidepsin. METHODS: Eligible patients with refractory, advanced solid tumors received elisidepsin as 24-h intravenous infusion every 3 weeks. Pharmacokinetic profiles were analyzed during cycles 1 and 2. RESULTS: Forty-two patients received elisidepsin at doses from 0.5 to 6.8 mg/m(2). The MTD was 6.8 mg/m(2), and the RD was 5.5 mg/m(2). Cohort expansion at the RD was done at a fixed dose (FD) of 10 mg, considered equivalent to 5.5 mg/m(2). DLTs (reversible grade 3 transaminase increases) occurred at 6.8 mg/m(2) (n = 2 patients), 5.5 mg/m(2) (n = 1), and 10 mg FD (n = 1). One patient with esophageal adenocarcinoma achieved complete response for >38 months, and 12 patients had disease stabilization (8 for ≥3 months). Median time-to-progression for these 12 patients was 4.8 months. Plasma elisidepsin concentrations increased with dose. No drug accumulation between cycles was found. No correlation was observed between body surface area (BSA) and plasma clearance; therefore, elisidepsin was given as flat dose (in mg) in the expansion cohort at the RD and in ongoing clinical trials. CONCLUSIONS: Elisidepsin is well tolerated with predictable reversible transaminase increases. Encouraging preliminary evidence of antitumor activity was observed.

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

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.

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.

PURPOSE: Spisulosine is a marine compound that showed antitumor activity in preclinical studies. We report results of a phase I trial performed in patients with advanced solid tumors with the marine compound, with the aim to determine the maximum tolerated dose (MTD) of a weekly 3-h intravenous (iv.) infusion, and to evaluate the safety, efficacy, and pharmacokinetics (PK) of the compound. PATIENTS AND METHODS: Two centers contributed 25 patients to the trial, and 7 dose levels were explored. RESULTS: In dose levels ranging from 4 to 128 mg/m²/day, no dose-limiting toxicities (DLT) were observed. One patient had DLT at 200 mg/m², a reversible grade 3 ALT increase. The MTD was not reached due to early termination of the Spisulosine trial program but is considered to be likely in the range of 200 mg/m² for this schedule. Drug-related adverse reactions included mild to moderate nausea, pyrexia, injection site reactions, and vomiting. One case of grade 4 peripheral motor and sensory neuropathy associated with general weakness and pain was observed during treatment cycle 4 and possibly contributed to the death of the patient. Grade 3 laboratory abnormalities included anemia and lymphopenia and increases in liver enzymes (alkaline phosphatase, transaminases, and bilirubin). Objective responses were not observed, and only four patients had short-lasting stable disease (<3 months). The PK data indicated a wide distribution, a long residence time, and dose proportionality of the agent. CONCLUSIONS: Hepato- and neuro-toxicity are schedule independent dose-limiting adverse events for this marine compound, as illustrated by this and other early clinical trials.

Mechanism-based pharmacokinetic/pharmacodynamic meta-analysis of trabectedin (ET-743, Yondelis) induced neutropenia.

Myelosuppression was found to be one of the main toxicities of trabectedin (ET-743, Yondelis) during phase I/II studies. Our objective was to develop a pharmacokinetic-pharmacodynamic (PK/PD) model that describes the time course of the absolute neutrophil counts (ANCs) in cancer patients receiving trabectedin. Data from 699 patients who received intravenous trabectedin as monotherapy (dose range: 0.006-1.8 mg/m2) as a 1-, 3-, or 24-h infusion every 21 days; 1- or 3-h infusion on days 1, 8, and 15 every 28 days; or a 1-h infusion daily for 5 consecutive days every 21 days were used to develop (N=405; ANCs=7,291) and validate (N=294; ANCs=5,029) the model. The PK/PD model comprised a trabectedin-sensitive progenitor cell compartment, linked to the peripheral blood compartment, through three transition compartments representing the maturation chain in the bone marrow. To capture the rebound effect due to endogenous growth factors, the model included a feedback mechanism. The model estimated three system-related parameters: ANC at baseline (Circ0), mean transit time in bone marrow (MTT), and a feedback parameter (gamma). A first-order process quantified by the rate constant k(e0) described the trabectedin concentrations at the effect compartment (C(e)), which were assumed to reduce the proliferation rate and/or to increase the killing rate of the progenitor cells according to the function alphaC(e)beta. The model was qualified and simulations were undertaken to evaluate the neutropenia schedule dependency and the effects of selected covariates. NONMEM software was used to perform the modeling and simulation analyses. For a typical man of 70 kg, the mean values (between-subject variability; %) of the Circ0, MTT, gamma, k(e0), alpha, and beta were estimated to be 4.46 x 10(9)/l (37.9%), 4.0 days (37.5%), 0.218 (41.8%), 2.09 h(-1) (77.9%), 2.00 l/microg (85.1%), and 1.26, respectively. Although in women, k(e0) was reduced by 29% and a 25% increase in body weight resulted in a 12.6% reduction in the beta parameter, the clinical relevance of these effects is limited. The model evaluation procedure indicated accurate prediction of the observed incidence of neutropenia grades 3 and 4 across the dosing regimens evaluated. Simulations indicated that trabectedin dose and interdose interval, but not infusion duration, are the main determinants of the neutropenia severity. The model-predicted time course of the ANC and its variability confirmed that neutropenia is reversible, of short duration, and non-cumulative. The extent and time course of neutropenia following six different dosing regimens of trabectedin were well predicted by the semiphysiological PK/PD model.