title: 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.
authors.affiliation: Sheba Medical Center, Tel HaShomer, Israel.
authors.forename: Talia
authors.initials: T
authors.lastname: Golan
authors.affiliation: Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: Tal
authors.initials: T
authors.lastname: Grenader
authors.affiliation: Lipomedix Pharmaceuticals Ltd., Jerusalem, Israel.
authors.forename: Patricia
authors.initials: P
authors.lastname: Ohana
authors.affiliation: Lipomedix Pharmaceuticals Ltd., Jerusalem, Israel.
authors.forename: Yasmine
authors.initials: Y
authors.lastname: Amitay
authors.affiliation: Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: Hilary
authors.initials: H
authors.lastname: Shmeeda
authors.affiliation: Texas Tech University Health Sciences Center-School of Pharmacy, Abilene, Texas.
authors.forename: Ninh M
authors.initials: NM
authors.lastname: La-Beck
authors.affiliation: Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: Esther
authors.initials: E
authors.lastname: Tahover
authors.affiliation: Sheba Medical Center, Tel HaShomer, Israel.
authors.forename: Raanan
authors.initials: R
authors.lastname: Berger
authors.affiliation: Shaare Zedek Medical Center, Jerusalem, Israel.|Lipomedix Pharmaceuticals Ltd., Jerusalem, Israel.|Hebrew University-School of Medicine, Jerusalem, Israel.
authors.forename: Alberto A
authors.initials: AA
authors.lastname: Gabizon
mesh_terms: D000328:Adult; D000368:Aged; D000740:Anemia / Q000139:chemically induced; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D008081:Liposomes; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D016685:Mitomycin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D009369:Neoplasms / Q000188:drug therapy*; D011092:Polyethylene Glycols; D011355:Prodrugs / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D066066:Response Evaluation Criteria in Solid Tumors; D013921:Thrombocytopenia / Q000139:chemically induced
chemical_list: D000903:Antibiotics, Antineoplastic; D008081:Liposomes; D011355:Prodrugs; D011092:Polyethylene Glycols; D016685:Mitomycin
keywords: Clinical trial; liposome; mitomycin C; prodrug