cis-Bis-neodecanoato-trans-R,R-1,2-diaminocyclohexanephlatinum(II) (NDDP) is a liposome dependent cisplatin analogue since the liposome carrier is required for its i.v. administration and for its biological activity. A Phase I study of liposome entrapped NDDP (L-NDDP) was performed using a single i.v. injection every 4 weeks. L-NDDP was prepared and characterized at M. D. Anderson Cancer Center. The maximum tolerated dose of L-NDDP was 312.5 mg/m2. The dose-limiting toxicity was myelosuppression, affecting all three blood cell lineages. The granulocyte nadir occurred on days 14–18, and the platelet nadir consistently earlier (days 11–12). The median day of recovery of blood cell counts was day 21 (range, 18–32). Other toxicities included grade 2 nausea and vomiting, fever consisting of a single temperature spike in most patients, grade 1 diarrhea after 60% of courses, and grade 1–2 malaise lasting for 5–10 days after the infusion in 73% of courses. Transient alanine aminotransferase elevations without clinical relevance were common. No signs of renal dysfunction or ototoxicity were observed. One patient with a preexisting peripheral neuropathy showed some progression of the neuropathy after a cumulative dose of 1605 mg/m2. Except for fever and transient liver dysfunction, no liposome related side effects were observed in spite of the high doses of lipid administered. The blood clearance of L-NDDP fits a two-compartment model at lower doses and a single-compartment model at the maximum tolerated dose, suggesting that saturation of the reticuloendothelial organs occurs at the maximum tolerated dose. Two minimal responses were observed. L-NDDP has a toxicity profile similar to that of carboplatin. Phase II studies to address the issue of how the therapeutic index of platinum compounds is affected by liposome entrapment are being planned.

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Supported in part by NIH Grants CA 45423 (R. P-S.) and CA 41581 (A. R. K.) and a Grant from The Liposome Company, Inc., Princeton, NJ.

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