Phase I and pharmacokinetic study of mitomycin C and celecoxib as potential modulators of tumor resistance to irinotecan in patients with solid malignancies.

PURPOSE: Based on the preclinical evidence of topoisomerase I (Topo-1) upregulation by mitomycin C(MMC) and decreased NF-kappaB activation by celecoxib, we evaluated combinations of irinotecan/MMC and irinotecan/MMC/celecoxib in patients with advanced solid malignancies. PATIENTS-METHODS: Initially, patients received MMC on day 1 and irinotecan on days 2, 8, 15 and 22, every 6 weeks. MMC dose was fixed at 6 mg/m(2) and cumulative doses of >36 mg/m(2) were not permitted. Irinotecan was escalated in 25 mg/m(2) increments. Due to late-onset diarrhea, the schedule was subsequently shortened to 4 weeks, omitting irinotecan on days 15 and 22. In the second part of the study, celecoxib 400 mg orally twice daily was added to irinotecan/MMC regimen. Potential pharmacokinetic interactions and Topo-1 and DT-diaphorase (NQ01) gene expressions in peripheral-mononuclear cells were evaluated. RESULTS: Forty-five patients were enrolled. Irinotecan 125 mg/m(2) on days 2 and 8 in combination with MMC 6 mg/m(2) on day 1 every 4 weeks is recommended for future studies; myelosuppression and diarrhea are dose-limiting. The addition of celecoxib resulted in unacceptable toxicities despite reductions on irinotecan's dose. No relevant pharmacokinetic interactions occurred between irinotecan and MMC, and mean increases in Topo-1, were observed. Sixteen of 36 patients evaluable for response-assessment had discernable anti-tumor activity, including 1 complete, 4 partial, 10 minor and 1 tumor marker response. Four patients had prolonged (>4 months) disease-stability (stable disease, not included in CR or PR). Patients experiencing complete and partial responses had higher increments in Topo-1 expression. CONCLUSIONS: Modulation of irinotecan by MMC is feasible, devoid of pharmacological interactions and active in solid malignancies. The lack of improvement in therapeutic index does not support the addition of celecoxib.

Genotypic and allelic frequencies of SULT1A1 polymorphisms in women receiving adjuvant tamoxifen therapy.

Human sulfotransferase 1A1 (SULT1A1) is involved in the metabolism of a number of substances including 4-hydroxytamoxifen. It has been shown that patients who are homozygous for the variant SULT1A1 *2/*2 have lower catalytic activity. Previous data has suggested that patients with this particular genotype may be at a greater risk of developing breast cancer or not responding to tamoxifen therapy. To date, there is no data within the Hispanic population on the genotypic and allelic frequencies of the SULT1A1 gene. Two hundred and ninety-six patients were genotyped by either restriction fragment length polymorphism (RFLP) or Pyrosequencing for the SULT1A1 exon 7 polymorphism. The genotypic frequency was 0.47 (*1/*1), 0.40 (*1/*2) and 0.13 (*2/*2) in Caucasians and 0.37 (*1/*1), 0.45 (*1/*2) and 0.18 (*2/*2) in Hispanics. Although Hispanics have a higher genotypic frequency of variant genotypes this difference was not statistically significant (p=0.26). SULT1A1 genotype did not correlate with any prognostic or predictive markers associated with breast cancer. Future evaluations will assess the functional significance of this polymorphism on survival.

Phase I and pharmacokinetic study of irofulven, a novel mushroom-derived cytotoxin, administered for five consecutive days every four weeks in patients with advanced solid malignancies.

PURPOSE: To evaluate the toxicity and pharmacologic behavior of the novel mushroom-derived cytotoxin irofulven administered as a 5-minute intravenous (IV) infusion daily for 5 days every 4 weeks to patients with advanced solid malignancies. PATIENTS AND METHODS: In this phase I trial, 46 patients were treated with irofulven doses ranging from 1.0 to 17.69 mg/m(2) as a 5-minute IV infusion (two patients received a 1-hour infusion) daily for 5 days every 4 weeks. The modified continual reassessment method was used for dose escalation. Pharmacokinetic studies were performed on days 1 and 5 to characterize the plasma disposition of irofulven. RESULTS: Forty-six patients were treated with 92 courses of irofulven. The dose-limiting toxicities on this schedule were myelosuppression and renal dysfunction. At the 14.15-mg/m(2) dose level, renal dysfunction resembling renal tubular acidosis occurred in four of 10 patients and was ameliorated by prophylactic IV hydration. The 17.69-mg/m(2) dose level was not tolerated because of grade 4 neutropenia and renal toxicity, whereas the 14.15-mg/m(2) dose level was not tolerable with repetitive dosing because of persistent thrombocytopenia. Other common toxicities included mild to moderate nausea, vomiting, facial erythema, and fatigue. One partial response occurred in a patient with advanced, refractory metastatic pancreatic cancer lasting 7 months. Pharmacokinetic studies of irofulven revealed dose-proportional increases in both maximum plasma concentrations and area under the concentration-time curve, while the agent exhibited a rapid elimination half-life of 2 to 10 minutes. CONCLUSION: Given the results of this study, the recommended dose of irofulven is 10.64 mg/m(2) as a 5-minute IV infusion daily for 5 days every 4 weeks. The preliminary antitumor activity documented in a patient with advanced pancreatic cancer and the striking preclinical antitumor effects of irofulven observed on intermittent dosing schedules support further disease-directed evaluations of this agent on the schedule evaluated in this study.

Pharmacokinetics and bioequivalence of a combined oral formulation of eniluracil, an inactivator of dihydropyrimidine dehydrogenase, and 5-fluorouracil in patients with advanced solid malignancies.

BACKGROUND: This study was performed to evaluate the pharmacokinetics, bioequivalence, and feasibility of a combined oral formulation of 5-flurouracil (5-FU) and eniluracil (Glaxo Wellcome Inc., Research Triangle Park, North Carolina), an inactivator of dihydropyrimidine dehydrogenase (DPD). The rationale for developing a combined eniluracil/5-FU formulation oral dosing form is to simplify treatment with these agents, which has been performed using separate dosing forms, and decrease the probability of severe toxicity and/or suboptimal therapeutic results caused by inadvertently high or conversely insufficient 5-FU dosing. PATIENTS AND METHODS: The trial was a randomized, three-way crossover bioequivalence study of three oral dosing forms of eniluracil/5-FU tablets in adults with solid malignancies. Each period consisted of two days of treatment and a five- to seven-day washout phase. Eniluracil at a dose of 20 mg, which results in maximal DPD inactivation, was administered twice daily on the first day and in the evening on the second day of each of the three treatments. On the morning of the second day, all patients received a total eniluracil dose of 20 mg orally and a total 5-FU dose of 2 mg orally as either separate tablets (treatment A) or combined eniluracil/5-FU tablets in two different strengths (2 tablets of eniluracil/5-FU at a strength (mg/mg) of 10/1 (treatment B) or 8 tablets at a strength of 2.5/0.25 (treatment C)). The pharmacokinetics of plasma 5-FU, eniluracil, and uracil, and the urinary excretion of eniluracil, 5-FU, uracil, and alpha-fluoro-beta-alanine (FBAL), were studied. To determine the bioequivalence of the combined eniluracil/5-FU dosing forms compared to the separate tablets, an analysis of variance on pharmacokinetic parameters reflecting eniluracil and 5-FU exposure was performed. RESULTS: Thirty-nine patients with advanced solid malignancies had complete pharmacokinetic studies performed during treatments A, B, and C. The pharmacokinetics of eniluracil and 5-FU were similar among the three types of treatment. Both strengths of the combined eniluracil/5-FU dosing form and the separate dosing forms were bioequivalent. Mean values for terminal half-life, systemic clearance, and apparent volume of distribution for oral 5-FU during treatments A/B/C were 5.5/5.6/5.6 hours, 6.6/6.6/6.5 liters/hour, and 50.7/51.5/50.0 liters, respectively. The intersubject coefficient of variation for pharmacokinetic variables reflecting 5-FU exposure and clearance in treatments ranged from 23% to 33%. The urinary excretion of unchanged 5-FU over 24 hours following treatments A, B, and C averaged 52.2%, 56.1%, and 50.8'%, of the administered dose of 5-FU, respectively. Parameters reflecting DPD inhibition, including plasma uracil and urinary FBAL excretion following treatments A, B, and C were similar. Toxicity was generally mild and similar following all three types of treatments. CONCLUSIONS: The pharmacokinetics of 5-FU and eniluracil were similar and met bioequivalence criteria following treatment with the separate oral formulations of 5-FU and eniluracil and two strengths of the combined formulation. The availability of a combined eniluracil/5-FU oral dosing form will likely simplify dosing and decrease the probability of severe toxicity or suboptimal therapeutic results caused by an inadvertent 5-FU overdose or insufficient 5-FU dosing in the case of separate oral formulations, thereby enhancing the overall feasibility and 0therapeutic index of oral 5-FU therapy.

Phase I and pharmacokinetic study of the differentiating agent vesnarinone in combination with gemcitabine in patients with advanced cancer.

PURPOSE: To evaluate the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetic profile of vesnarinone given once daily in combination with gemcitabine. PATIENTS AND METHODS: Twenty-six patients were treated with oral vesnarinone once daily on a continuous schedule at doses of 60, 90, 120, 150, and 180 mg in combination with intravenous (IV) gemcitabine at a dose of 1,000 mg/m(2) on days 1, 8, and 15 every 4 weeks. To determine whether biologically relevant concentrations were being achieved, predose concentrations (C(min)) of vesnarinone were obtained weekly. Plasma gemcitabine and 2',2'-difluorodeoxyuridine concentrations were obtained during courses 1 and 2. RESULTS: Twenty-six patients were treated with 92 courses of vesnarinone/gemcitabine. The principal toxicities of the regimen consisted of neutropenia and thrombocytopenia, which were dose-limiting in two of eight heavily pretreated new patients treated at the 90 mg/1,000 mg/m(2) dose level and one of 10 minimally pretreated new patients at the 120 mg/1,000 mg/m(2) dose level. None of three patients treated with 15 courses at the vesnarinone/gemcitabine dose levels of 60 mg/1,000 mg/m(2) experienced DLT. Pharmacokinetic studies of vesnarinone revealed significant interpatient variability at any given dose level. There was evidence of a linear relationship between vesnarinone dose and mean C(min) at dosages of vesnarinone less than 150 mg, with plateauing of mean C(min) values at higher dosages. There was no impact of vesnarinone on gemcitabine concentrations, and the vesnarinone pharmacokinetics did not change with gemcitabine between weeks 1 and 2. Two partial responses occurred in patients with refractory breast and non-small-cell lung carcinoma. CONCLUSION: When combined with gemcitabine, the recommended dose of vesnarinone for phase II evaluations is 90 mg orally once daily with gemcitabine 1,000 mg/m(2) IV on days 1, 8, and 15 every 4 weeks. There is no evidence of pharmacokinetic interaction between vesnarinone and gemcitabine. Further studies of vesnarinone as a single agent or in combination with gemcitabine and other antineoplastic agents are warranted.

Oral paclitaxel and concurrent cyclosporin A: targeting clinically relevant systemic exposure to paclitaxel.

Oral paclitaxel is not inherently bioavailable because of the overexpression of P-glycoprotein by intestinal cells and the significant first-pass extraction by cytochrome P450-dependent processes. This study sought to simulate the toxicological and pharmacological profile of a clinically relevant schedule of paclitaxel administered on clinically relevant i.v. dosing schedules in patients with advanced solid malignancies using oral paclitaxel administered with cyclosporin A, an inhibitor of both P-glycoprotein and P450 CYP3A. Nine patients were treated with a single course of oral paclitaxel in its parenteral formulation at a paclitaxel dose level of 180, 360, or 540 mg. Cyclosporin A was administered at a dose of 5 mg/kg p.o. 1 h before and concurrently with oral paclitaxel. Blood sampling was performed to evaluate the pharmacokinetics of paclitaxel, 6-alpha-hydroxypaclitaxel, 3-p-hydroxypaclitaxel, and cyclosporin A. The pharmacokinetic behavior of paclitaxel was characterized using both compartmental and noncompartmental methods. Model-estimated parameters were used to simulate paclitaxel concentrations after once daily and twice daily oral administration of paclitaxel and cyclosporin A. Aside from an unpleasant taste, the oral regimen was well tolerated, and there were no grade 3 or 4 drug-related toxicities. The systemic exposure to paclitaxel, as assessed by maximum plasma concentration (Cmax) and area under the plasma concentration versus time curve (AUC) values, did not increase as the dose of paclitaxel was increased from 180 to 540 mg, and there was substantial interindividual variability (4-6-fold) at each dose level. Mean paclitaxel Cmax values approached plasma concentrations achieved with clinically relevant parenteral dose schedules, averaging 268+/-164 ng/ml. AUC values averaged 3306+/-1977 ng x h/ ml, which was significantly lower than AUC values achieved with clinically relevant i.v. paclitaxel dose schedules. However, computer simulations using pharmacokinetic parameters derived from the present study demonstrated that pharmacodynamically relevant steady-state plasma paclitaxel concentrations of at least 0.06 microM would be achieved after protracted once daily and twice daily dosing with oral paclitaxel and cyclosporin A. Paclitaxel metabolites were detectable in three patients, and the 6-alpha-hydroxypaclitaxel: paclitaxel and 3-p-hydroxypaclitaxel:paclitaxel AUC ratios averaged 0.63 and 0.86, respectively; these values were substantially higher than values reported in patients treated with i.v. paclitaxel. Oral paclitaxel was bioavailable in humans when administered in combination with oral cyclosporin A 5 mg/kg 1 h before and concurrently with paclitaxel treatment, and plasma paclitaxel concentrations achieved with this schedule were biologically relevant and approached concentrations attained with clinically relevant parenteral dose schedules. However, treatment of patients with oral paclitaxel using a single oral dose administration schedule failed to achieve sufficiently high systemic drug exposure and pharmacodynamic effects. In contrast, computer simulations demonstrated that clinically relevant pharmacodynamic effects are likely to be achieved with multiple once daily and twice daily oral paclitaxel-cyclosporin A dosing schedules.

DX-8951f, a hexacyclic camptothecin analog, on a daily-times-five schedule: a phase I and pharmacokinetic study in patients with advanced solid malignancies.

PURPOSE: To assess the feasibility of administering DX-8951f (exatecan mesylate), a water-soluble, camptothecin analog, as a 30-minute intravenous infusion daily for 5 days every 3 weeks, determine the maximum-tolerated dose (MTD) and pharmacokinetic (PK) behavior of DX-8951f, and seek preliminary evidence of anticancer activity. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of DX-8951f. After three patients were treated at the first dose level, doses were to be escalated in increments of 100%, using a single patient at each dose level unless moderate toxicity was observed. The MTD, defined as the highest dose level at which the incidence of dose-limiting toxicity did not exceed 20%, was calculated separately for minimally pretreated (MP) and heavily pretreated (HP) patients. The PK and excretory profiles of DX-8951, the anhydrous form of DX-8951f, were also characterized. RESULTS: Thirty-six patients were treated with 130 courses of DX-8951f at six dose levels ranging from 0.1 to 0.6 mg/m(2)/d. Brief, noncumulative neutropenia was the most common toxicity observed. Severe myelosuppression (neutropenia that was protracted and/or associated with fever and/or severe thrombocytopenia) was consistently experienced by HP and MP patients at doses exceeding 0.3 and 0.5 mg/m(2)/d, respectively. Nonhematologic toxicities (nausea, vomiting, and diarrhea) were also observed, but these effects were rarely severe. Objective antitumor activity included partial responses in one patient each with platinum-resistant extrapulmonary small-cell and fluoropyrimidine- and irinotecan-resistant colorectal carcinoma, and minor responses in patients with prostate, hepatocellular, thymic, primary peritoneal, and irinotecan-resistant colorectal carcinomas. The PKs of total DX-8951 were linear and well fit by a three-compartment model. CONCLUSION: The recommended doses for phase II studies of DX-8951f as a 30-minute infusion daily for 5 days every 3 weeks are 0.5 and 0.3 mg/m(2)/d for MP and HP patients, respectively. The characteristics of the myelosuppressive effects of DX-8951f, paucity of severe nonhematologic toxicities, and antitumor activity against a wide range of malignancies warrant broad disease-directed evaluations of DX-8951f on this schedule.

Phase I and pharmacologic study of PN401 and fluorouracil in patients with advanced solid malignancies.

PURPOSE: To assess the feasibility of administering PN401, an oral uridine prodrug, as a rescue agent for the toxic effects of fluorouracil (5-FU), and to determine the maximum-tolerated dose of 5-FU when given with PN401, with an 8-hour treatment interval between these agents. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of 5-FU, given as a rapid intravenous infusion weekly for 3 consecutive weeks every 4 weeks. PN401 was administered orally 8 hours after 5-FU administration, to achieve sustained plasma uridine concentrations of at least 50 micromol/L. Initially, patients received 6 g of PN401 orally every 8 hours for eight doses (schedule 1). When dose-limiting toxicity (DLT) was consistently noted, patients then received 6 g of PN401 every 2 hours for three doses and every 6 hours thereafter for 15 doses (schedule 2). RESULTS: Twenty-three patients received 50 courses of 5-FU and PN401. Among patients on schedule 1, DLT (grade 4 neutropenia complicated by fever and diarrhea) occurred in those receiving 5-FU 1,250 mg/m(2)/wk. Among patients on schedule 2, 5-FU 1,250 mg/m(2)/wk was well tolerated, but grade 4, protracted (> 5 days) neutropenia was consistently noted in those treated with higher doses of the drugs. Nonhematologic effects were uncommon and rarely severe. The pharmacokinetics of 5-FU, assessed in 12 patients on schedule 2, were nonlinear, with the mean area under the time-versus-concentration curve (AUC) increasing from 298 +/- 44 to 962 +/- 23 micromol/L and mean clearance decreasing from 34 +/- 4 to 15.6 +/- 0.38 L/h/m(2) as the dose of 5-FU was increased from 1,250 to 1,950 mg/m(2)/wk. 5-FU AUCs achieved with 5-FU 1,250 mg/m(2)/wk for 6 weeks along with the intensified PN401 dose schedule were approximately five-fold higher than those achieved with 5-FU alone. Plasma uridine concentrations increased with each of the three PN401 doses given every 2 hours, and uridine steady-state concentrations were greater than 50 micromol/L. CONCLUSION: Treatment with oral PN401 beginning 8 hours after 5-FU administration is well tolerated and results in sustained plasma uridine concentrations above therapeutic-relevant levels. The recommended 5-FU dosage for phase II evaluations is 1,250 mg/m(2)/wk for 3 weeks every 4 weeks with the intensified PN401 dose schedule (schedule 2). At this dose, systemic exposure to 5-FU as measured by AUC was five-fold higher than that observed after administration of a conventional 5-FU bolus.

A phase I and pharmacological study of protracted infusions of crisnatol mesylate in patients with solid malignancies.

This Phase I and pharmacological study was performed to assess the feasibility of administering the polycyclic aromatic hydrocarbon crisnatol in increasingly prolonged continuous i.v. infusions to patients with advanced solid malignancies. The study also sought to characterize the-principal toxicities of crisnatol on this schedule, to recommend doses for subsequent disease-directed studies, and to characterize possible associations between pharmacological parameters and toxicity. Sixteen patients were treated with 40 courses of crisnatol administered as a continuous i.v. infusion. The initial dose-schedule was 750 mg/m2/day for 6 days, and the duration of the infusion was to be progressively increased by 3-day increments to 9, 12, 15, 18, and 21. Courses were to be repeated every 4 weeks. Moderate to severe central nervous system (CNS) toxicity precluded the administration of crisnatol 750 mg/m2/day for longer than 6 days, and, therefore, the dose of crisnatol was reduced to 600 mg/m2/day. At this dose, three of five patients receiving a 12-day infusion experienced dose-limiting toxicity, which consisted of pulmonary thromboembolism (two patients) and grade 4 thrombocytopenia (one patient). None of the six patients completing a 9-day infusion at 600 mg/m2/day developed dose-limiting toxicity during the first or second course of crisnatol. At this dose level, the plasma concentrations at steady state (Css) averaged 1607.8+/-261.1 ng/ml, which exceeds minimal inhibitory concentrations for most tumors in vitro (1000 ng/ml). In fact, the administration of crisnatol at a dose of 600 mg/m2/day for 9 days resulted in the longest duration that biologically relevant plasma crisnatol concentrations have been sustained. Plasma Css values were significantly higher in patients who experienced severe CNS toxicity compared with those who did not (2465.3+/-1213.5 versus 1342+/-447.3 ng/ml; P = 0.04). There were no relationships evident between the clearance of crisnatol and indices reflecting renal and hepatic functions. One patient with a glioblastoma multiforme experienced a partial response lasting 14 months. The relative lack of intolerable CNS toxicity at the recommended dose for Phase II studies of crisnatol, 600 mg/m2/day for 9 days, as well as the magnitude of the Css values achieved and the antitumor activity observed at this dose, are encouraging. However, the mechanisms for the apparently increased thrombogenicity observed in this trial are unclear and require further elucidation.

Phase I and pharmacologic study of the tyrosine kinase inhibitor SU101 in patients with advanced solid tumors.

PURPOSE: To evaluate the clinical feasibility and pharmacologic behavior of the platelet-derived growth factor (PDGF) tyrosine kinase inhibitor SU101, administered on a prolonged, intermittent dosing schedule to patients with advanced solid malignancies. PATIENTS AND METHODS: Twenty-six patients were treated with SU101 doses ranging from 15 to 443 mg/m(2) as a 24-hour continuous intravenous (IV) infusion weekly for 4 weeks, repeated every 6 weeks. Pharmacokinetic studies were performed to characterize the disposition of SU101 and its major active metabolite, SU0020. Immunohistochemical staining of PDGF-alpha and -beta receptors was performed on malignant tumor specimens obtained at diagnosis. RESULTS: Twenty-six patients were treated with 52 courses (187 infusions) of SU101. The most common toxicities were mild to moderate nausea, vomiting, and fever. Two patients experienced one episode each of grade 3 neutropenia at the 333 and 443 mg/m(2) dose levels. Dose escalation of SU101 above 443 mg/m(2)/wk was precluded by the total volume of infusate required, 2.5 to 3.0 L. Individual plasma SU101 and SU0020 concentrations were described by a one-compartment model that incorporates both first-order formation and elimination of SU0020. SU101 was rapidly converted to SU0020, which exhibited a long elimination half-life averaging 19 +/- 12 days. At the 443 mg/m(2)/wk dose level, trough plasma SU0020 concentrations during weeks 2 and 4 ranged from 54 to 522 micromol/L. Immunohistochemical studies revealed PDGF-alpha and -beta receptor staining in the majority (15 of 19) of malignant neoplasms. CONCLUSION: SU101 was well tolerated as a 24-hour continuous IV infusion at doses of up to 443 mg/m(2)/wk for 4 consecutive weeks every 6 weeks. Although further dose escalation was precluded by infusate volume constraints, this SU101 dose schedule resulted in the achievement and maintenance of substantial plasma concentrations of the major metabolite, SU0020, for the entire treatment period.

Phase I and pharmacokinetic study of the oral fluoropyrimidine capecitabine in combination with paclitaxel in patients with advanced solid malignancies.

PURPOSE: To evaluate the feasibility of administering the oral fluoropyrimidine capecitabine in combination with paclitaxel, to characterize the principal toxicities of the combination, to recommend doses for subsequent disease-directed studies, and to determine whether significant pharmacokinetic interactions occur between these agents when combined. PATIENTS AND METHODS: Sixty-six courses of capecitabine and paclitaxel were administered to 17 patients in a two-stage dose-escalation study. Paclitaxel was administered as a 3-hour intravenous (IV) infusion every 3 weeks, and capecitabine was administered continuously as two divided daily doses. During stage I, capecitabine was escalated to a target dose of 1,657 mg/m(2)/d, whereas the paclitaxel dose was fixed at 135 mg/m(2). In stage II, paclitaxel was increased to a target dose of 175 mg/m(2), and the capecitabine dose was the maximum established in stage I. Pharmacokinetics were characterized for each drug when given alone and concurrently. RESULTS: Myelosuppression, predominately neutropenia, was the principal dose-limiting toxicity (DLT). Other toxicities included hand-foot syndrome, diarrhea, hyperbilirubinemia, skin rash, myalgia, and arthralgia. Two patients treated with capecitabine 1,657 mg/m(2)/d and paclitaxel 175 mg/m(2) developed DLTs, whereas none of six patients treated with capecitabine 1,331 mg/m(2)/d and paclitaxel 175 mg/m(2) developed DLTs during course 1. Pharmacokinetic studies indicated that capecitabine and paclitaxel did not affect the pharmacokinetic behavior of each other. No major antitumor responses were noted. CONCLUSION: Recommended combination doses of continuous capecitabine and paclitaxel are capecitabine 1,331 mg/m(2)/d and paclitaxel 175 mg/m(2)/d IV every 3 weeks. Favorable preclinical mechanistic interactions between capecitabine and paclitaxel, as well as an acceptable toxicity profile without clinically relevant pharmacokinetic interactions, support the performance of disease-directed evaluations of this combination.

Phase I and pharmacokinetic trial of oral irinotecan administered daily for 5 days every 3 weeks in patients with solid tumors.

PURPOSE: We conducted a phase I dose-escalation trial of orally administered irinotecan (CPT-11) to characterize the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetic profile, and antitumor effects in patients with refractory malignancies. PATIENTS AND METHODS: CPT-11 solution for intravenous (IV) use was mixed with CranGrape juice (Ocean Spray, Lakeville-Middleboro, MA) and administered orally once per day for 5 days every 3 weeks to 28 patients. Starting dosages ranged from 20 to 100 mg/m2/d. RESULTS: Grade 4 delayed diarrhea was the DLT at the 80 mg/m2/d dosage in patients younger than 65 years of age and at the 66 mg/m2/d dosage in patients 65 or older. The other most clinically significant toxicity of oral CPT-11 was neutropenia. A linear relationship was found between dose, peak plasma concentration, and area under the concentration-time curve (AUC) for both CPT-11 and SN-38 lactone, implying no saturation in the conversion of irinotecan to SN-38. The mean metabolic ratio ([AUC(SN-38 total) + AUC(SN-38G total)]/AUC(CPT-11 total)) was 0.7 to 0.8, which suggests that oral dosing results in presystemic conversion of CPT-11 to SN-38. An average of 72% of SN-38 was maintained in the lactone form during the first 24 hours after drug administration. One patient with previously treated colorectal cancer and liver metastases who received oral CPT-11 at the 80 mg/m2/d dosage achieved a confirmed partial response. CONCLUSION: The MTD and recommended phase II dosage for oral CPT-11 is 66 mg/m2/d in patients younger than 65 years of age and 50 mg/m2/d in patients 65 or older, administered daily for 5 days every 3 weeks. The DLT of diarrhea is similar to that observed with IV administration of CPT-11. The biologic activity and favorable pharmacokinetic characteristics make oral administration of CPT-11 an attractive option for further clinical development.

A phase I and pharmacokinetic study of losoxantrone and paclitaxel in patients with advanced solid tumors.

A Phase I and pharmacological study was performed to evaluate the feasibility, maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics of the anthrapyrazole losoxantrone in combination with paclitaxel in adult patients with advanced solid malignancies. Losoxantrone was administered as a 10-min infusion in combination with paclitaxel on either a 24- or 3-h schedule. The starting dose level was 40 mg/m2 losoxantrone and 135 mg/m2 paclitaxel (as a 24- or 3-h i.v. infusion) without granulocyte colony-stimulating factor (G-CSF). Administration of these agents at the starting dose level and dose escalation was feasible only with G-CSF support. The following dose levels (losoxantrone/paclitaxel, in mg/m2) of losoxantrone and paclitaxel as a 3-h infusion were also evaluated: 50/135, 50/175, 50/200, 50/225, and 60/225. The sequence-dependent toxicological and pharmacological effects of losoxantrone and paclitaxel on the 24- and 3-h schedules of paclitaxel were also assessed. The MTD was defined as the dose at which >50% of the patients experienced DLT during the first two courses of therapy. DLTs, mainly myelosuppression, occurring during the first course of therapy were noted in four of six and five of eight patients treated with 40 mg/m2 losoxantrone and 135 mg/m2 paclitaxel over 24 and 3 h, respectively, without G-CSF. DLTs during the first two courses of therapy were observed in one of six patients at the 50/175 (losoxantrone/paclitaxel) mg/m2 dose level, two of four patients at the 50/200 mg/m2 dose level, one of four patients at the 50/225 mg/m2 dose level, and two of five patients at the 60/225 mg/m2 dose level. The degree of thrombocytopenia was worse, albeit not statistically significant, when 24-h paclitaxel preceded losoxantrone, with a mean percentage decrement in platelet count during course 1 of 80.7%, compared to 43.8% with the reverse sequence (P = 0.19). Losoxantrone clearance was not significantly altered by the sequence or schedule of paclitaxel. Cardiac toxicity was observed; however, it was not related to total cumulative dose of losoxantrone. An unacceptably high rate of DLTs at the first dose level of 40 mg/m2 losoxantrone and 135 mg/m2 paclitaxel administered as either a 24- or 3-h i.v. infusion precluded dose escalation without G-CSF support. The addition of G-CSF to the regimen permitted further dose escalation without reaching the MTD. Losoxantrone at 50 mg/m2 followed by paclitaxel (3-h i.v. infusion) at 175 mg/m2 with G-CSF support is recommended for further clinical trials.

Alternative dosing schedules for irinotecan.

Most of the clinical experience with irinotecan (CPT-11 [Camptosar]) has been with either a weekly or an every-3-week schedule. Recent phase I trials have explored new routes and schedules of administration. One approach attempts to maximize dose frequency and intensity by giving irinotecan every 2 weeks. A phase I trial of this approach is now complete and has led to a phase II trial in patients with recurrent colorectal cancer. Data suggest that smaller doses of a topoisomerase I inhibitor administered repeatedly may result in greater antitumor activity than large doses administered intermittently. A phase I trial has been performed in adults in which irinotecan was administered daily for 5 consecutive days, followed by 2 days off, for 2 weeks out of 3. Similar trials are under way in children. Oral administration, another strategy that has undergone phase I testing, has several theoretical advantages:(1) The acidic pH of the stomach favors maintenance of irinotecan in the active lactone ring form. (2) Irinotecan is more rapidly and extensively converted to SN-38 by tissue carboxylesterases found in high concentrations in the gut and liver. (3) Low doses can be delivered over a protracted period. (4) The oral route enhances patient convenience. These alternative dosing schedules may facilitate integration of irinotecan into combination chemotherapy and combined-modality treatment regimens.

Phase I and pharmacokinetic study of paclitaxel in combination with biricodar, a novel agent that reverses multidrug resistance conferred by overexpression of both MDR1 and MRP.

PURPOSE: To evaluate the feasibility of administering biricodar (VX-710; Incel, Vertex Pharmaceuticals Inc, Cambridge, MA), an agent that modulates multidrug resistance (MDR) conferred by overexpression of both the multidrug resistance gene product (MDR1) P-glycoprotein and the MDR-associated protein (MRP) in vitro, in combination with paclitaxel. The study also sought to determine the maximum-tolerated dose (MTD) of paclitaxel that could be administered with biologically relevant concentrations of VX-710 and characterize the toxicologic and pharmacologic profiles of the VX-710/ paclitaxel regimen. PATIENTS AND METHODS: Patients with solid malignancies were initially treated with VX-710 as a 24-hour infusion at doses that ranged from 10 to 120 mg/m2 per hour. After a 2-day washout period, patients were re-treated with VX-710 on an identical dose schedule followed 8 hours later by paclitaxel as a 3-hour infusion at doses that ranged from 20 to 80 mg/m2. The pharmacokinetics of both VX-710 and paclitaxel were studied during treatment with VX-710 alone and VX-710 and paclitaxel. Thereafter, patients received VX-710 and paclitaxel every 3 weeks. RESULTS: VX-710 alone produced minimal toxicity. The toxicologic profile of the VX-710/paclitaxel regimen was similar to that reported with paclitaxel alone; neutropenia that was noncumulative was the principal dose-limiting toxicity (DLT). The MTD levels of VX-710/ paclitaxel were 120 mg/m2 per hour and 60 mg/m2, respectively, in heavily pretreated patients and 120/60 to 80 mg/m2 per hour in less heavily pretreated patients. At these dose levels, VX-710 steady-state plasma concentrations (Css) ranged from 2.68 to 4.89 microg/mL, which exceeded optimal VX-710 concentrations required for MDR reversal in vitro. The pharmacokinetics of VX-710 were dose independent and not influenced by paclitaxel. In contrast, VX-710 reduced paclitaxel clearance. At the two highest dose levels, which consisted of VX-710 120 mg/m2 per hour and paclitaxel 60 and 80 mg/m2, pertinent pharacokinetic determinants of paclitaxel effect were similar to those achieved with paclitaxel as a 3-hour infusion at doses of 135 and 175 mg/m2, respectively. CONCLUSION: VX-710 alone is associated with minimal toxicity. In combination with paclitaxel, biologically relevant VX-710 plasma concentrations are achieved and sustained for 24 hours, which simulates optimal pharmacologic conditions required for MDR reversal in vitro. The acceptable toxicity profile of the VX-710/ paclitaxel combination and the demonstration that optimal pharmacologic conditions for MDR reversal are achievable support a rationale for further trials of VX710/paclitaxel in patients with malignancies that are associated with de novo or acquired resistance to paclitaxel caused by overexpression of MDR1 and/or MRP.

A phase I trial of human corticotropin-releasing factor (hCRF) in patients with peritumoral brain edema.

BACKGROUND: Human corticotropin-releasing factor (hCRF) is an endogenous peptide responsible for the secretion and synthesis of corticosteroids. In animal models of peritumoral brain edema, hCRF has significant anti-edematous action. This effect, which appears to be independent of the release of adrenal steroids, appears mediated by a direct effect on endothelial cells. We conducted a feasibility and phase I study with hCRF given by continuous infusion to patients with brain metastasis. PATIENTS AND METHODS: Peritumoral brain edema documented by MRI and the use of either no steroids or stable steroid doses for more than a week were required. MRIs were repeated at completion of infusion and estimations by dual echo-image sequence (Proton density and T2-weighted images) of the amount of peritumoral edema were performed. The study was performed in two stages. In the feasibility part, patients were randomized to receive either 0.66 or 1 microgram/kg/h of hCRF or placebo over 24 hours. The second part was a dose finding study of hCRF over 72 hours at escalating doses. RESULTS: Seventeen patients were enrolled; only one was receiving steroids (stable doses) at study entrance; dose-limiting toxicity (hypotension) was observed at 4 micrograms/kg/h x 72 hours in two out of four patients, while zero of five patients treated at 2 micrograms/kg/h developed dose-limiting toxicities. Flushing and hot flashes were also observed. Improvement of neurological symptoms and/or exam were seen in 10 patients. Only small changes were detected by MRI. Improvement in symptoms did not correlate with changes in cortisol levels, and changes in cortisol levels were not correlated with changes in peritumoral edema. CONCLUSIONS: hCRF is well tolerated in doses up to 2 micrograms/kg/h by continuous infusion x 72 hours. Hypotension limits administration of higher doses. The observation of clinical benefit in the absence of corticosteroids suggests hCRF may be an alternative to steroids for the treatment of patients with peritumoral brain edema. Further exploration of this agent in efficacy studies is warranted.

Docetaxel in combination with fluorouracil: study design and preliminary results.

The relatively recent introduction of a new class of chemotherapeutic agents--the taxoids--has raised hope of improved survival for patients with advanced or metastatic cancer. Following encouraging preclinical results of taxoid combinations, this phase I, nonrandomized trial was designed to evaluate a 1-hour intravenous infusion of docetaxel (Taxotere) on day 1 combined with fluorouracil (5-FU) as a daily intravenous bolus for 5 consecutive days. To date, 27 patients with advanced solid neoplasms have received 86 courses of docetaxel/5-FU at the following dose levels: 25/100, 35/150, 50/200, 60/200, and 60/300 mg/m2. Preliminary results showed no unexpected toxicities, and the principal toxicity was neutropenia of short duration. A treatment regimen of 60 mg/m2 docetaxel on day 1 and 300 mg/m2 of 5-FU given for 5 days, with a single course length of 28 days, is projected as the maximum tolerated dose.

New anticancer agents in clinical development.

A better understanding of the biology and biochemistry of the cancer cell has led to the development of various promising new antineoplastic compounds that are now undergoing phase I, II, and III clinical testing. These drugs include topoisomerase I inhibitors, such as camptothecin and its analogs 9-aminocamptothecin, irinotecan, and topotecan; and the paclitaxel analog docetaxel. The authors discussed these new agents last month. In Part 2 of their article, they describe gemcitabine, an antimetabolite structurally related to cytarabine; fluorouracil prodrugs and other thymidylate synthase (TS) inhibitors, and new approaches to anticancer therapy, such as angiogenesis inhibitors, differentiating agents, signal transduction inhibitors, and gene therapy.

New anticancer agents in clinical development.

A better understanding of the biology and biochemistry of the cancer cell has led to the development of various promising new antineoplastic compounds that are now undergoing phase I, II, and III clinical testing. These drugs include topoisomerase I inhibitors, such as camptothecin and its analogs 9-aminocamptothecin, irinotecan, and topotecan; the paclitaxel analog docetaxel; gemcitabine, an antimetabolite structurally related to cytarabine; and fluorouracil prodrugs and other thymidylate synthase (TS) inhibitors. Another exciting approach to cancer treatment is the use of agents that induce a less malignant state by altering cellular phenotype. Such agents include angiogenesis inhibitors, differentiating agents, signal transduction inhibitors, and gene therapy.