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Executive Summary

Lederle's enloplatin is considered a "very promising" platinum-based agent for treating solid tumors by the MD Anderson Cancer Center, Timothy Madden, Pediatric Division clinical research specialist, told the Houston cancer center's Fourteenth Annual Pharmacy Symposium on Cancer Chemotherapy, held Oct. 11-13. "The big promise for enloplatin [is] non-cross resistance" with the established anticancer agents cisplatin and carboplatin (Bristol-Myers Squibb's Platinol and Paraplatin), Madden said. Researchers at the cancer center consider enloplatin to be "the most active platinum anticancer drug against leukemia," symposium materials state. Madden added that there are "a number of platinum-containing agents that are likely to have as much promise." About 400 platinum complexes are currently being investigated, he said. Madden spoke, along with Virginia Eaton, University of California- San Francisco and a visiting scientist at Genentech, on "Treatment Options for Solid Tumors: Role of New Agents." "What has given a lot of hope to investigators of [enloplatin] came from the preclinical activity of this agent. There are numerous in vitro cell lines including cisplatin-resistant L1210 and P388 leukemias that were very sensitive to enloplatin," the MD Anderson researcher explained. Lederle said the drug is being studied in a single-center Phase II trial in ovarian cancer patients and a Phase I/II trial for refractory lymphoma and chronic lymphocytic leukemia. MD Anderson is conducting Phase I/II trials in ovarian cancer patients and expects leukemia trials to begin "shortly," according to symposium materials. Although results from Phase I trials, conducted in Europe, suggest that enloplatin is "considerably" less toxic than cisplatin, there were some reports of severe nephrotoxicity in patients treated with enloplatin, "most of whom had prior cisplatin exposure but for whom that type of total renal failure was not expected," Madden said. Because of the toxicities, the center is not conducting a simple Phase II trial. MD Anderson is beginning the ovarian cancer trial at a dose of 750 mg/m[2] and will increase the dose, "controlling the drugs that patients receive and supplement to their therapy and at the same time looking at sensitive and specific markers for renal toxicity to determine whether or not that is truly linked to the use of this agent, or whether it was just an anomaly in a few patients who had life-threatening renal failure," Madden said. The maximum tolerated dose determined in the European Phase I studies was 1,227 mg/m[2]. The dose-limiting toxicity of enloplatin is usually myelosuppression; unlike carboplatin's DLT, the myelosuppression is usually neutropenia, rather than thrombocytopenia. "The use of growth factors may well allow us to dose-escalate this and to ameliorate this dose-limiting toxicity," Madden noted. The most frequent adverse event seen in enloplatin treatment is nausea and vomiting. Toxicities with a low incidence rate include acute fever (not associated with neutropenia), reported in about 3% of patients, and diarrhea and hepatotoxicity, reported in less than 2% of patients. "This is somewhat similar to what has been reported in high-dose carboplatin therapy, in which patients have succumbed to fetal hepatonecrosis," Madden noted. MD Anderson investigators also are "excited" about Burroughs Wellcome's Navelbine (vinorelbine). It has "substantial oral absorption," with about 25% oral bioavailability, unlike other vinca alkaloids, and has "shown considerable activity in patients with breast cancer and with non-small cell lung cancer who were known to be resistant to vinca alkaloids," Madden said. Navelbine has "demonstrated synergy with cisplatin and etoposide [Bristol-Myers Squibb's VePesid], which is very important for the lung cancer patients because these are quite often used for their known synergistic action," Madden said. "In fact, some of the highest non-small cell response rates [have been seen] in using these two agents combined and now with the addition of vinorelbine the dose response rates have been increased." Navelbine, for which B-W licensed U.S. and Canadian rights from Pierre Fabre Medicament in 1989, is being studied in Phase II/III trials in both I.V. and oral formulations for non-small cell lung, breast, ovarian, renal, head and neck, prostate and testicular cancer, according to symposium materials. MD Anderson is studying Navelbine in Phase I pediatric trials in both I.V. and oral doses. The vinca alkaloid has "relatively little neurotoxicity, but is as potent an inhibitor of the polymerization of [mitotic]tubules as vincristine [Lilly's Oncovin], which remains the most active of the vincas." The dose-limiting tolerance of Navelbine is myelosuppression, "predominantly neutropenia, which is really good," Madden noted. Toxicity is "somewhat lower than what we see with vinblastine, but somewhat higher than we see with vincristine." There are "some reports of hepatotoxicity, very few of neuropathy." Because neuropathy is less than with other vincas, "it's hoped that for diseases in which all of the liver therapy can't be delivered to the patient due to these neurogenic toxicities...higher dose intensity will be able to be given." The dose-limiting GI toxicity seen with Navelbine, most often in the oral formulation, was diarrhea. Several other anticancer compounds derived from plant substances also were highlighted at the symposium as promising drugs in anticancer clinical trials. SmithKline Beecham's topotecan and CPT-11 (Daiichi's Irinotecan) are among the camptothecan compounds currently under development. The modification in topotecan's chemical structure that differentiates it from other camptothecans "improves water solubility, improves oral stability...and gives the compound less toxicity," UCSF's Eaton asserted. SmithKline Beecham is investigating the compound in Phase II trials in ovarian, breast, colorectal and lung cancer. NCI is studying topotecan in pediatric cancers. Eaton cautioned that in Phase I trials at MD Anderson, "patients who were heavily pretreated with other chemotherapies [did] not tolerate topotecan as well as less treated patients." The starting dose for Phase II trials in adult patients is 10 mg/m[2]. Eaton noted that the cancer center is currently dosing adults with a 15 mg/m[2] I.V. dose followed by treatment with G-CSF (Amgen's Neupogen) white blood cell stimulating factor "and that is getting some of the patients through," although some have "experienced some very severe...myelosuppression." In Phase I trials conducted at MD Anderson in leukemia patients, the DLT was mucocytis. The Daiichi camptothecan CPT-11 is distinguished by an active metabolyte -- SN-38 -- that has equal activity to its parent, Eaton noted. Studies also show "good synergy" of CPT-11 with cisplatin, ara-c (Upjohn's Cytosar) and mitomycin (Bristol-Myers' Mutamycin), she added. The "most exciting" CPT-11 Phase II results are from a study of the compound in gynecologic malignancies, which was "able to document five complete remissions with a minimum duration of up to 75 days," Eaton said. While complete remission was not achieved in studies in other cancers, "most investigators felt that survival was prolonged in the patients with end-stage disease, and the quality of life was prolonged," she said. Phase I/II trials are ongoing and "they suggest good activity in solid tumors and hematologic malignancies," Eaton said. Most of the trials are being conducted in Japan. Taxol, the yew-tree derived anticancer agent from Bristol- Myers Squibb, may need some modifications, MD Anderson's Madden suggested. He noted that the agent, "like a number of poorly water soluble agents, is solubilized in the Cremophor, or polyoxyethylated castor oil medium," which results in a number of hypersensitivity reactions with symptoms such as dyspnea, erythema and hypotension. "I think what needs to be developed is probably better solubilizing agents for delivery," Madden suggested. The semisynthetic taxol analog Taxotere (Rhone-Poulenc Rorer) does not use Cremophor. Madden noted that in the trials of Taxotere which recently begun at MD Anderson, he has not seen a hypersensitivity reaction.

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