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

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. Mitomycin C is a potent alkylating agent infrequently used by the systemic route due to its cumulative myelosuppression and other problematic adverse events. This study found that a pegylated liposomal prodrug of mitomycin C is tolerated at ~3‐fold greater dose than equivalent doses of mitomycin C, has a long circulation time, and may be active in a variety of tumor types.