Pegylated liposomal mitomycin C prodrug enhances tolerance of mitomycin C: a phase 1 study in advanced solid tumor patients

Abstract

Mitomycin C (MMC) has potent cytotoxicity but cumulative toxicity limits widespread use. In animals, pegylated liposomal mitomycin C lipid-based prodrug (PL-MLP) was well tolerated and more effective than free MMC. We evaluated PL-MLP in patients with advanced cancer. Twenty-seven patients were treated in escalating dose cohorts of 0.5-3.5 mg/kg (equivalent to 0.15-1.03 mg/kg MMC) every 4 weeks for up to 12 cycles, unless disease progression or unacceptable toxicity occurred. Pharmacokinetics were assessed during cycles 1 and 3. Per protocol maximum tolerated dose was not reached at 3.5 mg/kg. However, prolonged thrombocytopenia developed after repeated doses of 3 mg/kg or cumulative doses of 10-12 mg/kg. Dose-related grade 3 or higher adverse events included fatigue, anemia, and decreased platelets. Cmax and AUC0-∞ increased linearly over the dose range 0.5-2.0 mg/kg, and greater than linearly from 2.5 to 3.5 mg/kg; there were no significant differences in clearance of MLP between cycles 1 and 3. Median t1/2 was 23 h among dose cohorts, with no trend by dose or cycle. One patient had a partial response. Stable disease was observed in 10 patients across all dose levels. PL-MLP has a long circulation time, was well tolerated, and can be administered to heavily pretreated patients at a single dose of 3.0 mg/kg and cumulative dose of 10-12 mg/kg before development of prolonged thrombocytopenia; this is nearly threefold the equivalent dose of MMC tolerated historically. This formulation may be active in a variety of tumor types and is better tolerated than free MMC.

Trial registration: ClinicalTrials.gov NCT01705002.

Keywords: Clinical trial; liposome; mitomycin C; prodrug.

© 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Figures

Figure 1

Relative (%) change in platelet counts from pretreatment count (normalized to 100) across the various dose levels and along the first three cycles. (A) Mean % change; (B) Median % change. Note the downward trend for both mean and median values. The 3.0 and 3.5 mg/kg dose cohorts fall below 50% after the third cycle. Mean and Median values followed a similar pattern. For clarity, SEM values were not plotted.

Figure 2

Platelet Counts as a function of cumulative dose of PL-MLP in seven patients receiving extended treatment (beyond three cycles). Gray area marks Grade 2–4 toxicity zone for low platelets. Note the downward trend of platelet counts as cumulative dose increases.

Figure 3

Pharmacokinetics of PL-MLP. (A) Changes in PK parameters as a function of dose level. Note the nonlinearity in Cmax and AUC for dose levels is >2 mg/kg. There was no perceptible change in t1/2 with dose, but there was a slight reduction in clearance and volume of distribution with increasing dose. The third cycle of Cohort 3.5 mg/kg was given at a dose of 3 mg/kg and was therefore not plotted. (B) Clearance of MLP following PL-MLP administration to dose cohorts 0.5–2 mg/kg. Note the monophasic exponential clearance in the first 72 h. There was no noticeable difference in the clearance of MLP between the first and third cycles. Each color line represents an individual. Values of MLP < 1 mg/L were plotted but not used for analysis of PK parameters.

Figure 4

Survival of all 27 PL-MLP-treated patients entered to the study. Records from start of study (Nov 2012) to last data check (Nov 2014). Median survival of all patients (N = 27) and of responding (black ticks, SD + PR) patients (N = 11) was 5.6 and 9.7 months, respectively.

Figure 5

Antitumor activity of PL-MLP. (A) CT image showing response to treatment in a melanoma patient with disappearance of ascites and volume shrinkage of abdominal tumor mass (>30%) for 6 months. Reported as Stable Disease (as two small lesions in lung and forehead—not shown—increased in size). (B) Plot showing CEA decreases in a colon cancer patient receiving 12 cycles of PL-MLP. From start of PL-MLP, the CEA level dropped gradually by >2-fold. Stable Disease in CT-scan for 12+ months.