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Manuel Hidalgo, MD
Continued research into the underlying mechanisms of neoplasia and metastasis are providing new targets for drug development. A session on Wednesday (September 15) on clinical pharmacology focused on data from early clinical trials with these new compounds in patients with cancer. In addition, data regarding the use of current chemotherapy in patients with liver dysfunction were presented.
Angiogenesis Inhibitors SU5416 and PTK/ZK
Angiogenesis, the formation of new blood vessels, is one of the principal characteristics of malignant tumors and represents a recently identified target for cancer therapy. Dr. O'Donell from the Royal Marsden Hospital in London presented data from a phase I clinical trial with the vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor SU5416 in patients with solid malignancies. The investigators treated 19 patients with various doses of this agent on a twice-a-week treatment regimen. Doses up to 190 mg/m2 were tolerable and resulted in only minor toxic effects. This result has been seen by other investigators who conducted similar trials. Because SU5416 is an angiogenesis inhibitor, these investigators elegantly incorporated an evaluation of tumor blood flow in their clinical trial using gadolinium-enhanced magnetic resonance imaging (MRI). Although the results are still preliminary, patients with stable tumors apparently had decreased tumor blood flow.[1]
Dr. Dreuvs from the Tumor Biology Center and Department of Oncology, Freiburg, Germany, presented data on a second VEGF TK inhibitor for oral administration, PTK787/ZK222584 (PTK/ZK). Similarly, the agent was very well-tolerated and resulted in only minor toxicity. Pharmacologic analysis demonstrated that the agent was rapidly absorbed from the gastrointestinal tract and, at the doses explored, resulted in plasma concentrations well above the concentration required in animal models for antitumor efficacy.[2] No data were presented on potential biological surrogate markers of activity, although the investigator stated their intention to analyze it. These two compounds are still in the very preliminary phase of their development, and results from ongoing studies are eagerly awaited.
ET-743
Dr. Twelves from Glasgow University presented a compiled pharmacokinetic/pharmacodynamic analysis of 5 phase I clinical trials conducted with ET-743, a novel marine-derived compound. ET-743. This molecule has a complex and versatile mechanism of action that has not yet been fully characterized, although it is clear that the compound binds to the minor groove of DNA. Preclinical studies demonstrated substantial antitumor activity, and the agent has just completed phase I evaluation using different schedules of administration.
Overall, ET-743 resulted in a tolerable toxicity profile, which consisted mainly of myelosuppression, fatigue, and transient and reversible elevation in liver enzymes. The toxicity of the agent seemed to be ameliorated by prolonged (3-24 hour) intravenous infusion versus more rapid (1-hour) infusion schedules. Pharmacokinetic analysis consistently demonstrated that at the recommended phase II doses, ET-743 administration resulted in plasma drug concentration that exceed the concentrations required in vitro for antitumor activity. In addition, and more important, ET-743 treatment was associated with therapeutic responses in patients with several disease types, particularly sarcoma. Based on better drug tolerability and perhaps higher exposure, the drug is currently being evaluated in phase II clinical trials in patients with sarcomas using 24-hour continuous infusion. Results from these studies should be available in the near future and are highly anticipated.[3]
Matrix Metalloproteinase Inhibitor Bay-9556
Bay-9556 is an oral inhibitor of matrix metalloproteinases that appears to be very specific and highly potent. The drug has recently completed phase I studies and is currently being evaluated in phase II-III clinical trials. The phase I trial showed that Bay 9556 is well-tolerated and produces minimal toxicity. The recommended dose for phase II and III clinical trials is 800 mg orally twice a day.
Dr. Seymour, on behalf of the National Cancer Institute of Canada, presented the preliminary results of a phase I clinical trial in which Bay-9556 was combined with either 5-fluorouracil or doxorubicin. The combination with 5-fluorouracil at doses of 350 mg/m2 per day for 5 consecutive days resulted in dose-limiting thrombocytopenia that could not be attributed to a pharmacokinetic interaction. Bay-9556 at 400 mg orally bid in combination with 5-fluorouracil at 350 mg/m2 per day for 5 consecutive days seemed to be well-tolerated. On the other hand, full doses of Bay-9556 were tolerable in combination with doxorubicin at 60 mg/m.2 However, while the combination of Bay-9556 and 5-fluorouracil did not result in any pharmacokinetic interaction, Bay 9556 increased plasma levels of doxorubicin by 30%-40%. The optimal use of compounds such as Bay-9556 will probably be in combination chemotherapy. The increase in doxorubicin levels secondary to Bay-9556 administration needs to be taken into account because this could potentially increase toxicity, particularly cardiotoxicity.[4]
Nucleoside Analog Troxacitabine
Troxacitabine (BCH-4556) is a novel nucleoside analog with an unusual L-configuration. The agent is phosphorylated intracellularly to its triphosphate metabolite that is incorporated into the nascent DNA strain. The metabolic product of troxacitabine phosphorylation is not a substrate of DNA polymerase and results in DNA chain termination.
Dr. Belanger from the National Cancer Institute of Canada and Dr. Hidalgo from the Institute for Drug Development, San Antonio, Texas, presented data from two phase I clinical trials of troxacitabine administered either as a 30-minute infusion day 1 every 21 days or as a daily x 5 infusion every 28 days.[5,6] The principal toxicities have been myelosuppression and cutaneous toxicity, both as rashes and hand-foot syndrome. Toxicity seemed to be more pronounced in patients with prior exposure to chemotherapy and radiation therapy. The recommended phase II doses were 10 mg/m2 on day 1 every 21 days, or 1.2 and 1.5 mg/m2 for heavily pretreated and lightly pretreated subjects, respectively. The agent demonstrated activity in patients with renal cell carcinoma, carcinoma with an unknown primary, and melanoma, and is currently undergoing evaluation in phase II clinical trials in patients with different malignant diseases. In addition, troxacitabine is being evaluated in phase I clinical trials in combination with conventional agents such as cisplatin and paclitaxel. This agent has unique antitumoral and pharmacological properties and has the potential to become an important anticancer agent.
Irinotecan in Patients With Liver Dysfunction
Irinotecan (CPT-11) is an active agent in patients with colorectal carcinoma and has became the standard of care for patients with this disease. CPT-11 is converted to its metabolic product by a series of enzymatic reactions catalyzed by hepatic enzymes. The majority of patients with colon cancer will develop liver metastasis at some point in their medical course, and these patients frequently have liver dysfunction. However, the metabolism and toxicity of CPT-11 in this subset of patients has not been defined.
Dr. Raymond from the Institute Gustave Roussy, France, presented data from a phase I pharmacologic study of CPT-11 in patients with various grades of liver dysfunction. They reported that patients with moderate to severe liver dysfunction developed dose-limiting toxicities at 240 mg/m2, which are below the usually recommended dose of 350 mg/m2. There was a parallel relation between high bilirubin levels and CPT-11 clearance. In addition, these patients have substantially higher plasma levels of CPT-11 active metabolites, which could explain the observance of higher toxicity despite reduce dose levels.[6]
References
- O'Donnell A, Trigo JM, Walker R, et al. A phase I trial of SU5416 a novel angiogenesis inhibitor in solid tumours, incorporating MRI assessment of vascular permeability. Abstracts and Proceedings from ECCO10. Sept 12-16, 1999; Vienna, Austria. Abstract 1134.
- Drevs J, Mross K, Reusch P, et al. Phase I dose escalation, pharmacokinetic (pk) study of a novel vascular endothelial growth factor (VEGF) receptor inhibitor, PTK787ZK 222584 (PTK/ZK). Abstracts and Proceedings from ECCO10. Sept 12-16, 1999; Vienna, Austria. Abstract 1137.
- Twelves C, Misset JL, Villalona-Calero MA, et al. Phase I trials with ET-743, a marine derivative (MD) anticancer agent. Abstracts and Proceedings from ECCO10. Sept 12-16, 1999; Vienna, Austria. Abstract 1135.
- Hirte H, Steward D, Goel R, et al. NCIC CTG IND 113: Two phase I dose escalation pharmacokinetic (PK) studies of Bay-9556 (Bay) in combination with either doxorubicin (DOX) or modulated 5-fluorouracil (5-FU). Abstracts and Proceedings from ECCO10. Sept 12-16, 1999; Vienna, Austria. Abstract 1136.
- Moore M, Belanger K, Jolivet J, et al. NCIC CTG IND 103: A phase I and pharmacokinetic study of the novel L-nucleoside analog troxacitabine (BCH-4556) given every 21 days. Abstracts and Proceedings from ECCO10. Sept 12-16, 1999; Vienna, Austria. Abstract 1140.
- Stephenson J, Baker SD, Simmons C, et al. Phase I and pharmacokinetic (PK) study of troxacitabine (b-Lldioxolan-cytidine; BCH-4556) on a daily x 5 day every 4-week schedule. Abstracts and Proceedings from ECCO10. Sept 12-16, 1999; Vienna, Austria. Abstract 1139.
- Raymound E, Vernillet L, Boige V, et al. Phase I dose finding study with irinotecan (CPT-11) in cancer patients with hepatic dysfunction. Abstracts and Proceedings from ECCO10. Sept 12-16, 1999; Vienna, Austria. Abstract 1138.
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