7111 Background: DHA-paclitaxel (Taxoprexin [TXP]) is a covalent conjugate of paclitaxel and docosahexanoic acid that has greater tumour specificity in pre-clinical models than paclitaxel. It accumulates in tumour tissue where it is cleaved to paclitaxel. The objective of this multi-centre study was to determine the efficacy and tolerability of TXP as first line therapy in advanced NSCLC. Methods: A total of 44 patients (pts) [29 male, 15 female, median age 61y (range 39–74) PS 0 (11pts) PS 1 (33pts)] with pathologically confirmed stage IIIB or IV NSCLC and no previous cytotoxic treatment were enrolled. Pts were required to have adequate renal, hepatic and bone marrow function and have measurable disease. TXP was administered iv over 2 hours q21 days at one of two doses, 900 mg/m2 (31pts) and 1100 mg/m2 (13pts). Due to excess toxicity, including one toxic death, the starting dose was reduced to 900 mg/m2. As of November 2003 four pts remain on follow-up. Results: Twenty-eight courses (mean 2.1) were administered in the 1100 mg/m2 cohort and 109 courses (mean 3.5) for 900 mg/m2. Neutropenia was the primary toxicity and was dose related; 21 of 31 (68%) of patients treated at 900 mg/m2 had grade 3 or 4 neutropenia while 10 of 13 (77%) at 1100 mg/m2 had these grades of neutropenia. No grade 3 or 4 nausea /or vomiting, stomatitis or neuropathies were observed. Forty patients were evaluable for response: 900 mg/m2 PR 2/30 (6.7%), SD 13/30 (43%); 1100 mg/m2 PR 0/10 (0%), SD 3/10 (30%). Survival (see table) at the 900 mg/m2 dose level was comparable to that seen with standard platinum based combination chemotherapy. (Supported by American Regent.) Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Protarga, Inc. Luitpold Pharmaceuticals

The podophyllotoxin derivatives etoposide and teniposide are active in the treatment of a variety of malignant conditions. Both represent chemical modifications of podophyllin, an extract of Podophyllum peltatum (May apple, mandrake, Indian apple, wild lemon, or duck's foot), a plant long used as a folk remedy and recognized in the 19th century to be effective in the treatment of cancer. While etoposide is active in the treatment of many cancers and is widely used, it has a number of limitations due to its lack of water solubility. Etoposide phosphate (Etopophos; Bristol-Myers Squibb Company, Princeton, NJ) is a water-soluble prodrug of etoposide that is rapidly and completely converted to the parent compound after intravenous dosing. The pharmacokinetic profile of etoposide after treatment with either etoposide or etoposide phosphate is identical. Toxicity and clinical activity also are the same. Because etoposide phosphate is water soluble and can be made up to a concentration of 20 mg/mL, however, it can be given as a 5-minute bolus, in high doses in small volumes, and as a continuous infusion. Furthermore, it is not formulated with polyethylene glycol, polysorbate 80 (Tween; ICI Americas, Wilmington, DE), and ethanol, and does not cause acidosis when given at high doses. The easier-to-use etoposide phosphate represents an improved formulation of etoposide.

PURPOSE The purpose of this study was to determine the bioavailability (F) of etoposide (E;VP-16) after oral administration of the water-soluble prodrug etoposide phosphate (EP;BMY-40481) during a phase I trial in cancer patients. PATIENTS AND METHODS Twenty-nine patients received oral EP (capsules, 50 to 150 mg/m2/d of E equivalent) for 5 days in week 1 (course 1), followed every 3 weeks thereafter by a daily intravenous (i.v.) infusion for 5 days of E (80 mg/m2, 1-hour i.v. infusion; course 2); in three patients, the i.v. E course was given before oral EP. Plasma and urine E pharmacokinetics (high-performance liquid chromatography [HPLC]) were performed on the first day of oral EP administration and on the first day of i.v. E. RESULTS Twenty-six of 29 patients completed two courses or more, whereas three patients received only one course due to toxicity. Myelosuppression was dose-dependent and dose-limiting, with grade 4 leukoneutropenia in four of 15 patients at 125 mg/m2 and in five of seven patients at 150 mg/m2. One patient died of meningeal hemorrhage related to grade 4 thrombocytopenia. Other toxicities were infrequent and/or manageable. No objective response was observed. The maximum-tolerated dose (MTD) is therefore 150 mg/m2, and the recommended oral dose of EP for phase II trials in this poor-risk patient population is 125 mg/m2. Twenty-six patients had pharmacokinetic data for both oral EP and i.v. E, whereas three had pharmacokinetic data on the i.v. E course only. After oral administration of EP, the pharmacokinetics of E were as follows: mean absorption rate constant (Ka), 1.7 +/- 1.7 h-1 (mean +/- SD); lag time, 0.3 +/- 0.2 hours; time of maximum concentration (t(max)), 1.6 +/- 0.8 hours; and mean half-lives (t1/2), 1.6 +/- 0.2 (first) and 10.3 +/- 5.8 hours (terminal); the increase in the area under the plasma concentration-versus-time curve (AUC) of E was proportional to the EP dose. After the 1-hour i.v. infusion of E, maximum concentration (C(max)) was 15 +/- 3 micrograms/mL; mean AUC, 88.0 +/- 22.0 micrograms.h/mL; mean total-body clearance (CL), 0.97 +/- 0.24 L/h/m2 (16.2 mL/min/m2); and mean t1/2, 0.9 +/- 0.6 (first) and 8.1 +/- 4.1 hours (terminal). The 24-hour urinary excretion of E after i.v. E was significantly higher (33%) compared with that of oral EP (17%) (P < .001). Significant correlation was observed between the neutropenia at nadir and the AUC of E after oral EP administration (r = .58, P < .01, sigmoid maximum effect [E(max)] model). The mean F of E after oral administration of EP in 26 patients was 68.0 +/- 17.9% (coefficient of variation [CV], 26.3%; F range, 35.5% to 111.8%). In this study, tumor type, as well as EP dose, did not significantly influence the F in E. There was no difference in F of E, whether oral EP was administered before or after i.v. E. Compared with literature data on oral E, the percent F in E after oral prodrug EP administration was 19% higher at either low ( < or = 100 mg/m2) or high ( > 100 mg/m2) doses. CONCLUSION Similarly to E, the main toxicity of the prodrug EP is dose-dependent leukoneutropenia, which is dose-limiting at the oral MTD of 150 mg/m2/d for 5 days. The recommended oral dose of EP is 125 mg/m2/d for 5 days every 3 weeks in poor-risk patients. Compared with literature data, oral EP has a 19% higher F value compared with oral E either at low or high doses. This higher F in E from oral prodrug EP appears to be a pharmacologic advantage that could be of potential pharmacodynamic importance for this drug.

Etoposide phosphate, a water soluble prodrug of etoposide, was evaluated at levels potentially useful in transplantation settings in patients with malignancies. For pharmacokinetic studies of etoposide phosphate in this phase I study, 21 patients with solid tumors were treated with etoposide phosphate given as etoposide equivalents of 250, 500, 750, 1000 and 1200 mg/m2 infused over 2 h on days 1 and 2, and G-CSF 5 μg/kg per day starting on day 3 until WBC was ≥10 000/μl. Qualitative, quantitative, and pharmacokinetic analysis was performed as reported previously. Rapid conversion of etoposide phosphate into etoposide by dephosphorylation occurred at all dosage levels without indication of saturation of phosphatases. Plasma levels (Cpmax) and area under the curve (AUC) of etoposide phosphate and etoposide demonstrated linear dose effects. For etoposide, plasma disposition demonstrated biphasic clearance, with mean T1/2α of 2.09±0.61 h, and T1/2β of 5.83±1.71 h. An AUC as high as 1768.50 μg.h/ml was observed at a dose of 1200 mg/m2. The total body clearance (TBC) showed an overall mean of 15.72±4.25 ml/min per m2, and mean volume of distribution (VDss) of 5.64±1.06 l/m2. The mean residual time (MRT) for etoposide was 6.24±1.61 h. In urine, etoposide but not etoposide phosphate, was identified with large quantitative variations (1.83% to 33.45% of injected etoposide equivalents). These results indicate that etoposide phosphate is converted into etoposide with the linear dose-related Cpmax and AUCs necessary for use of this agent at the high dosage levels needed in transplantation protocols. A comparison of pharmacokinetic parameters of high- dose etoposide with the values observed in our study with etoposide phosphate revealed comparable values for the clinically important Cpmax and AUCs, clearance, terminal T1/2 and MRT. In contrast to the use of etoposide, etoposide phosphate can be delivered in aqueous vehicles and therefore may offer the advantage of ease of administration.

Etoposide phosphate (EP) is a water-soluble derivative of etoposide (VP-16), a semisynthetic podophyllotoxin which is useful in the treatment of a wide variety of hematological malignancies and solid tumors. Because etoposide is poorly water soluble, it must be dissolved in a variety of organic solvents and given in relatively large volumes of saline. EP is rapidly converted to the parent drug in vivo and has been shown to be active in animal studies. We performed a phase I pharmacokinetic study in 27 patients. Three patients each received an etoposide-equivalent dose of 50 or 75 mg/m2 each day by i.v. bolus (5 min) daily for 5 days and 21 patients received a dose equivalent to 100 mg/m2 of etoposide each day for 5 days. Non-compartmental pharmacokinetic data were obtained for 22 of the patients. As with previous studies, EP behaves as a prodrug of etoposide. The Cmax (25.3–42.5 μg/ml) increased linearly, while AUCint (75.8–156 h μg/ml) of etoposide increased proportionately with dose (50–100 mg/m2 of etoposide equivalents). Time to achieve Cmax corresponded to the end of the 5 min injection, indicating a rapid formation of etoposide from EP. Mean etoposide phosphate/etoposide Cmax and AUCint ratios were 0.08 or less and 0.003, respectively, indicating that the major circulating molety in plasma was etoposide. Parameters such as MRT, T1/2, CL/F, CLR, Vss/F and %UR were dose independent. The toxicities of EP were virtually identical to those seen with etoposide, with dose-related myelosuppression, alopecia and stomatitis. Severe neutropenia was the dose-limiting toxicity. No significant problems with hypotension or allergic reactions were observed. No problems, difficulties or complications were observed as a result of bolus (5 min) administration. On the basis of phase I toxicity data, we recommend an etoposide equivalent starting dose of 100 mg/m2/day for 5 days in previously untreated patients who have an excellent performance status. In patients who have had one or more prior chemotherapy regimens, extensive prior radiation therapy or moderately impaired performance status, we recommend an etoposide phosphate starting dose of 75 mg/m2/day for 5 days with courses repeated at 3 week intervals.

PURPOSE To determine the toxicities, maximum-tolerated dose (MTD), and pharmacology of etoposide phosphate, a water-soluble etoposide derivative, administered as a 5-minute intravenous infusion on a schedule of days 1, 3, and 5 repeated every 21 days. PATIENTS AND METHODS Thirty-six solid tumor patients with a mean age of 63 years, performance status of 0 to 1, WBC count > or = 4,000/microL, and platelet count > or = 100,000/microL, with normal hepatic and renal function were studied. Doses evaluated in etoposide equivalents were 50, 75, 100, 125, 150, 175, and 200 mg/m2/d. Etoposide in plasma and urine and etoposide phosphate in plasma were measured by high-performance liquid chromatography (HPLC). Eleven of 36 patients were treated with concentrated etoposide phosphate at 150 mg/m2/d. RESULTS Grade I/II nausea, vomiting, alopecia, and fatigue were common. Leukopenia (mainly neutropenia) occurred at doses greater than 75 mg/m2, with the nadir occurring between days 15 and 19 posttreatment. All effects were reversible. Hypotension, bronchospasm, and allergic reactions were not observed in the first 25 patients. The MTD due to leukopenia was determined to be between 175 and 200 mg/m2/d. In 11 patients treated with concentrated etoposide phosphate, no local phlebitis was noted, but two patients did develop allergic phenomena. The conversion of etoposide phosphate to etoposide was not saturated in the dosages studied. Etoposide phosphate had peak plasma concentrations at 5 minutes, with a terminal half-life (t1/2) of 7 minutes. Etoposide reached peak concentrations at 7 to 8 minutes, with a t1/2 of 6 to 9 hours. Both etoposide phosphate and etoposide demonstrated dose-related linear increases in maximum plasma concentration (Cmax) and area under the curve (AUC). CONCLUSION Etoposide phosphate displays excellent patient tolerance in conventional dosages when administered as a 5-minute intravenous bolus. The suggested phase II dose is 150 mg/m2 on days 1, 3, and 5. The ability to administer etoposide phosphate as a concentrated, rapid infusion may prove of value both in the outpatient clinic and in high-dose regimens.

Etoposide phosphate (Etopophos, BMY-40481) is a water-soluble derivative of the widely used podophyllotoxin etoposide (VP-16). The phosphate ester renders the compound water-soluble, eliminating the need for formulation in polysorbate (Tween) 80, ethanol, and polyethylene glycol. As a result the compound can be given at high concentrations and as a bolus. In animals and in vitro, etoposide phosphate (EP) is rapidly and completely converted to VP-16. Clinical development of the i.v. formulation has focused on the identification of the maximum tolerated dose (MTD) and pharmacokinetic characteristics of the drug using a 5 daily dose schedule and a days 1, 3, and 5 schedule, with the drug being given over 30 or 5 (bolus) min. Myelosuppression was dose-limiting. Data from these trials show the rapid and complete conversion of EP to VP-16, a pharmacokinetic/pharmacodynamic relationship for myelosuppression and exposure to VP-16, and an MTD of 100 and 150 mg/m(2) (molar equivalent to VP-16) when EP is given daily for 5 days and on days 1, 3, and 5. respectively. A formal randomized trial has been conducted to show the pharmacokinetic comparability of EP and VP-16. In this trial, exposure to VP-16 was the same after the parenteral administration of equimolar doses of EP or VP-16. The feasibility of bolus dosing and treatment at high concentrations has been demonstrated, with no effects on the cardiovascular system being noted. Parenteral EP is pharmacokinetically and biologically equivalent to VP-16 and has the advantages of the elimination of potentially toxic excipients; more convenient administration; and ability to be given as a bolus, at high concentrations, and as a continuous infusion.

PURPOSE To determine whether combination chemotherapy is superior to single agents for recurrent/metastatic head and neck cancer, we compared the efficacy and toxicity of cisplatin (CP) and fluorouracil (5-FU), alone and in combination in a phase III trial. PATIENTS AND METHODS Two hundred forty-nine patients with recurrent head and neck cancer were randomized to one of three treatments: CP (100 mg/m2) and 5-FU (1 g/m2 x 4), CP, or 5-FU every 3 weeks. RESULTS The overall response rate to the combination (32%) was superior to that of CP (17%) or 5-FU (13%) (P = .035). Response was associated with good performance status (PS) but not with primary site, site of recurrence, histology, prior irradiation, or relative dose intensity. Median time to progression was less than 2.5 months, and there was no significant difference in median survival (5.7 months) among the groups. By multivariate analysis, patients with better PS and poorly differentiated tumors had superior survival. Hematologic toxicity and alopecia were worse in the combination arm. CONCLUSION Although the response rate to the combination of CP plus 5-FU was superior to that achieved with single agents, survival did not improve.

Between 1984 and 1989, 159 patients presenting with advanced germ cell cancer were entered on a randomized clinical trial comparing the efficacy and toxicity of etoposide and bleomycin and either standard-dose cisplatin (20 mg/m2 daily for 5 days) or high-dose cisplatin (40 mg/m2 daily for 5 days). Of the 159 patients, 153 were assessable for toxicity and response. As expected, patients receiving the high-dose cisplatin regimen experienced significantly more neurotoxicity, ototoxicity, nausea and vomiting, and myelo-suppression. Four patients (3%) died related to therapy. Despite the toxicity encountered, dose intensity was maintained. Overall, 84% of patients in the high-dose arm received 80% or more of the projected dose of cisplatin, etoposide, and bleomycin; and 90% of patients on the standard-dose arm received 80% or more of the projected dose. Of the 76 eligible patients randomized to receive the high-dose cisplatin regimen, 52 (68%) became disease-free with chemotherapy alone or with subsequent resection of residual teratoma or cancer. Of the 77 patients randomized to the standard-dose arm, 56 (73%) became disease-free with chemotherapy alone or with surgery. Median follow-up is now 24 months. Eleven patients (three high-dose and eight standard-dose) relapsed from disease-free status. Overall, 74% of patients receiving the high-dose cisplatin regimen are alive, and 63% are continuously free of disease. Of the patients receiving the standard-dose cisplatin regimen, 74% are alive, and 61% are continuously free of disease. This randomized prospective trial in advanced germ cell cancer achieved dose intensity of the most active single agent in this disease. This dose intensity did not translate into an improved survival or cure. We conclude that dose escalation of cisplatin beyond standard doses results in excess toxicity with no accompanying therapeutic benefit.