1 Department of Medical Oncology, Tumor Biology Center at the University of Freiburg; 2 Department of Internal Medicine and Medical Oncology, West German Cancer, University Medical School of Essen; 3 Humboldt University Medical School, Berlin; 4 Department of Hematology and Oncology, University Hospital Freiburg; 5 Bayer Healthcare, Pharma Research Center, Wuppertal, Germany
* Correspondence to: Dr Dirk Strumberg, MD, Department of Internal Medicine (Cancer Research), University Medical School of Essen, Hufelandstraße 55, 45122 Essen, Germany. Tel:+49-201-723-3138; Fax:+49-201-723-3138; Email: dirk.strumberg{at}uni-essen.de
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Abstract |
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Patients and methods: A total of 81 patients with advanced solid tumors were treated with BAY 38-3441 either at doses of 20, 40, 67, 100, 140, 210, 315, 470 and 600 mg/m2/day for 1 day every 3 weeks (single-dose schedule), or at doses of 126, 189, 246, 320 and 416 mg/m2/day once daily for three consecutive days every 3 weeks (3-day schedule). Plasma sampling was performed to characterize the pharmacokinetics of BAY 38-3441 and camptothecin with these schedules.
Results: DLTs included renal toxicity, granulocytopenia and thrombocytopenia on the single-day schedule at doses 470 mg/m2/day, and diarrhea and thrombocytopenia on the 3-day schedule at doses
320 mg/m2/day. Other non-DLTs were gastrointestinal, dermatological and hematological. Pharmacokinetics of BAY 38-3441 and camptothecin appear to be dose-dependent, but not linear.
Conclusions: Renal toxicity was dose-limiting for BAY 38-3441 using 30-min infusions on the single-dose schedule. Dose escalation to 470 mg/m2/day is feasible using a 2-h infusion. However, because of the superior safety profile, we recommend the 3-day schedule for BAY 38-3441 at a dose of 320 mg/m2/day as 30-min infusions for further phase II studies.
Key words: camptothecin glycoconjugate, phase I, topoisomerase I
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Introduction |
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CPT and analogs stabilize topoisomerase IDNA cleavage complexes [46
], leading to persisting single-stranded DNA breaks. During DNA synthesis (replication), stabilized cleavage complexes convert into cytotoxic DNA double-strand breaks, ultimately causing cell death [7
12
]. Because cytotoxicity is dependent upon expression of topoisomerase I and DNA replication [13
17
], cells in the S-phase of the cell cycle are 1000 times more sensitive to CPT than cells in other cellular phases [18
].
During early clinical trials, camptothecin administration was associated with severe side-effects. The water-soluble salt of camptothecin (carboxylate form) induced severe toxicity, which consisted of severe cumulative hematological toxicity, diarrhea and chemical or hemorrhagical cystitis, which were often formidable and unpredictable [19, 20
]. Numerous CPT derivatives with reduced toxicity compared with the original compound have been developed. Two CPT analogs are presently marketed: topotecan (HycamptinTM), and irinotecan (CamptosarTM). Topotecan was approved in 1996 for use as second-line therapy in ovarian cancer patients [21
]. Irinotecan was approved by the Food and Drug Administration (FDA) in 2000 as first-line treatment for advanced colorectal carcinoma [22
]. Other CPT analogs such as 9-aminocamptothecin (IDEC), 9-nitrocamptothecin (RFS-2000; Supergen), NX 211 (Lurtotecan; Nexstar) and others are in clinical development.
Although these analogs differ significantly in their anticancer activity and in their pharmaceutical and pharmacological profiles [1, 3
, 12
], they share the basic chemical structure of a heterocyclic five-member ring, with a lactone moiety on ring E (Figure 1) [1
, 2
, 10
12
]. In vitro and in vivo studies suggest that an intact lactone ring is essential for topoisomerase I inhibition. However, under physiological conditions (pH 7 or above), all CPTs undergo rapid and reversible non-enzymatic hydrolysis of the lactone ring to generate an open-ring hydroxy carboxylic acid (Figure 1A). In addition, human serum albumin preferentially binds the carboxylate form, driving the equilibrium to favor carboxylate formation [23
]. The t1/2 for conversion of the CPT lactone ring into the carboxylate form is 11 min, and in whole blood, only 5.3% of total CPT remains in the lactone form once equilibrium is established [24
]. Although the CPT carboxylate is more water soluble than the lactone, it is at least 10-fold less active as an inhibitor of topoisomerase I [25
]. Interestingly, the lactone form is more stable in mouse serum, which could explain why the marked efficacy of these compounds in nude mouse xenografts was not predictive of the clinical activity [26
]. Indeed, clinical activity appears to correlate with the level of CPT lactone present in human serum [1
, 3
].
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BAY 38-3441 is a topoisomerase I inhibitor that has a peptide-carbohydrate moiety attached to the CPT toxophore [28]. The chemical structure is illustrated in Figure 1B. BAY 38-3441 was selected through a screening process in which compounds were evaluated for lactone ring stability, in vitro activity in a panel of human tumor cell lines, in vivo antitumor activity, and favorable preliminary toxicological profile [28
]. The peptide-carbohydrate moiety confers increased water solubility and stability of the CPT lactone ring in plasma [28
]. In addition, the peptide-carbohydrate portion of the molecule is believed to be responsible for the selective uptake into tumor cells, which was measured by fluorescence microscopy using a chemically modified derivative [28
]. The active CPT toxophore splits from the peptide-carbohydrate intracellularly in lysosomal compartments, and/or extracellularly.
BAY 38-3441 demonstrated significant and dose-dependent antitumor efficacy against a broad range of tumor types. In animal models, BAY 38-3441 produced >1 log10 cell kill in three of the four models evaluated, including the MX-1 mammary and LXFL 529 lung tumor models. The MTD in these studies varied between 16 and 24 mg/kg/dose. It is worth noting that, at equitoxic dosages producing one drug death out of five mice, BAY 38-3441 caused a log10 cell kill and tumor growth delays more than double those of topotecan in the MX-1 mammary tumor model. In addition, 1.9 log10 cell kill and 375% growth delay were observed with the 24 mg/kg/dose of BAY 38-3441 compared with 0.9 log10 cell kill and a 190% growth delay for topotecan at 2.5 mg/kg/dose.
To determine the safety, toxicity and pharmacokinetics of this compound in patients with advanced cancer, we administered BAY 38-3441 either once every 3 weeks (single-dose schedule) or once daily for three consecutive days every 3 weeks (3-day schedule) in patients with advanced solid tumors.
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Patients and methods |
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Pre-treatment and follow-up studies
Pre-treatment evaluation consisted of a history and physical examination, complete blood cell count, serum chemistries, electrolytes and creatinine, PT and aPTT, urinalysis, electrocardiogram, chest X-ray and assessment of ECOG performance status. Blood counts and biochemical profiles were performed daily during the first week, then once weekly. Toxicity during each cycle was assigned according to the World Health Organization (WHO) toxicity grading scale. Lesions noted at baseline that were measured or evaluated by radiographic scan or X-ray were reviewed before each alternate course, and evaluated for response according to Response Evaluation Criteria in Solid Tumors (RECIST) and WHO criteria [29].
Drug administration
BAY 38-3441 [active compound: 20 (S)-200-{Na-[4-(3-0-methyl-ß-L-fucopyranosyloxy)-phenyl-amino-thiocarbonyl]-L-histidinyl-L-valyl}camptothecin] was manufactured by Bayer AG and supplied as a lyophilized powder in sterile 20 ml amber glass vials. Each vial contained 50 mg of the anhydrous free base. The lyophilized drug was reconstituted with 5% dextrose to a concentration of 5 mg/ml. This solution was diluted further with 5% dextrose in water to a final infusion volume of 50 or 100 ml. After reconstitution, BAY 38-3441 was infused over 30 min through either a central venous or peripheral catheter. Prophylactic intravenous or oral odansetron and metoclopramide were only administered in patients with a history of nausea or vomiting after previous BAY 38-3441 applications.
Study design
Two multicenter, prospective, non-blinded phase-I studies evaluating the safety profile of BAY 38-3441 were designed to assess the dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and BAY 38-3441 and CPT pharmacokinetics.
BAY 38-3441 was given as an infusion for 30 min, either on day 1 every 3 weeks (single-dose study) or once daily for three consecutive days every 3 weeks (3-day study). Dose escalation was performed until the MTD was reached. Cohorts of at least three patients entered each dose level. If no DLTs were observed after 2 weeks, the dose was escalated to the next level. Doses were doubled until a toxicity of grade 2 was observed, followed by a more conservative Fibonacci-like strategy. If one DLT occurred in one of the three patients, three additional patients were treated at the same dose level. If two DLTs were observed at a dose level, that dose was declared the MTD and no further dose escalation occurred. The recommended phase II dose was defined as one dose level below the MTD.
Patients continued treatment until disease progression or until unacceptable toxicity occurred (beyond study end, if applicable). Intra-individual dose escalation was not permitted in this study. A DLT was defined as the occurrence of any one of the following: (i) grade 3 non-hematologic toxicity, excluding alopecia and nausea/vomiting; (ii) platelet count <25 000/µl; or (iii) grade 4 neutropenia (absolute neutrophil count <500/µl) lasting >5 days and/or associated with fever (38.5°C). Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria (version 2.0).
Pharmacokinetic sampling and analysis
Blood and urine samples for determining the pharmacokinetic values of BAY 38-3441 and total CPT (lactone and carboxylate form) were obtained from all patients during the first cycle. Heparinized plasma samples (2.0 ml) were collected pre-treatment and 10, 20, 30, 35, 40, 45, 60, 75, 90, 120, 150 and 180 min, and 4, 6, 8, 10, 12, 15, 24, 36, 48, 72, 96 and 120 h after the start of the BAY 38-3441 infusion during the first week (single-dose schedule) or starting on day 3 of the first week (3-day schedule). All samples were immediately frozen at 20°C and stored at 70°C.
The free base form of the CPT glycoconjugate was measured in the plasma samples; however, for convenience in the text and tables, both the free base and HCl salt forms of the compound are designated as BAY 38-3441. Plasma samples were analyzed for BAY 38-3441 and CPT using a validated high performance liquid chromatography (HPLC) method with fluorescence detection. A 250 µl aliquot of each sample was mixed with 500 µl methanol containing 0.1 mg/l BAY 39-7770 as internal standard. Samples were centrifuged, and 400 µl of the supernatant were mixed with 20 µl of 0.5 M phosphoric acid. Of this mixture, 1550 µl were injected into the HPLC system.
The HPLC system consisted of a Hewlett Packard chromatograph series 1050 (Agilent) supplied with a Hewlett Packard degasser series 1100 (Agilent), and a fluorescence detector FLD 1100 (Agilent) set at 367 nm (excitation) and 428 nm (emission). The HPLC system was controlled by a HP DOS ChemStation Rev. A.02.05 (Agilent). The samples were chromatographed using a LiChrospher 100 RP-18 end-capped column (250 x 4 mm, 5 µm) (Merck). The mobile phase consisted of 10 mM phosphate buffer (pH 3.0) and methanol (68/32 v/v). The flow rate was 1.0 ml/min. The chromatograms were evaluated using the software CCW (Bayer AG). Calibration was performed on the basis of the ratios of peak heights of the analyte (BAY 38-3441 or CPT) with respect to the internal standard as a function of analyte concentration. The calibration line was obtained by linear regression with a weighting by 1/y2.
Each analytical series contained nine calibration samples in the working ranges of 101000 µg/l for BAY 38-3441 and of 1.0100 µg/l for CPT, as well as at least six quality control samples (three concentrations of each analyte in duplicate). The lower limits of quantification for urine as well as for plasma samples were 10 µg/l (BAY 38-3441) and 1.0 µg/l (CPT). Mean accuracy ranged from 97% to 110% with a precision of 3.8% to 7.0% for BAY 38-3441, and from 98% to 107% with a precision of 4.0% to 9.8% for CPT.
Pharmacokinetic evaluation
Pharmacokinetic parameters for BAY 38-3441 and total CPT (lactone and carboxylate form) were calculated by non-compartmental analysis using the software Kincalc (Bayer AG). Individual maximum concentration (Cmax) values were obtained directly from maximum plasma concentrations of individual profiles. Area under the drug concentration versus time curve (AUC) values were calculated applying the linear/logarithmic trapezoidal method within the range of quantifiable concentrations. The extrapolation to infinity was performed by dividing the last quantifiable concentration by the slope of the terminal logarithmic/linear regression line.
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Results |
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We subsequently analyzed the utility of a 3-day dosing schedule every 3 weeks, starting at a dose of BAY 38-3441 126 mg/m2/day (Table 3). One out of four patients experienced grade 3 elevation of alkaline phosphatase (ALP), which was considered unrelated to the study drug. At DL 246 mg/m2/day, one out of three patients showed mild renal toxicity by elevation of creatinine. Another patient showed grade 3 anemia that was due to progressive disease and bone marrow infiltration. Further dose escalation to DL 320 mg/m2/day was initially not associated with DLTs or any renal toxicity in three patients. Dose escalation to DL 416 mg/m2/day resulted in dose-limiting grade 4 diarrhea in one out of seven patients. Furthermore, all patients treated with BAY 38-3441 416 mg/m2/day presented grade 1/2 creatinine elevation that was not consistent with long-term clinical use of this dose. Consequently, 16 additional patients were added to the previous dose level to assess the safety and practical utility of the 320 mg/m2/day dose using the 3-day schedule (Table 3). Two of these patients experienced grade 3 diarrhea, which did not require hospitalization. Another patient experienced grade 4 diarrhea and grade 3 thrombocytopenia together with grade 3 anemia. It is noteworthy that this particular patient had a history of grade 3 myelosuppression during previous chemotherapy regimens. On the basis of these results, 320 mg/m2/day was defined as the recommended phase II dose (RPD) for BAY 38-3441 administered as a daily 30-min infusion for three consecutive days. In addition, pharmacokinetic determinations suggested that this schedule might be optimal with respect to the AUC(024 h) of both the parent compound BAY 38-3441 and CPT (see below).
Hematologic toxicities
Dose-limiting neutropenia and thrombocytopenia occurred with both the single-dose and 3-day schedules. None of the six patients on the single-dose schedule at DL 470 mg/m2 experienced any hematologic side-effects when BAY 38-3441 was infused for 30 min. However, extending the infusion to 2 h enhanced hematotoxicity at this dose level. One out of six patients experienced grade 3 neutropenia, grade 3 anemia and grade 4 thrombocytopenia, and three additional patients developed grade 23 anemia. Interestingly, dose escalation to 600 mg/m2 did not enhance hematologic side-effects further. Hematologic adverse events on the 3-day schedule included grade 3 thrombocytopenia and grade 3 anemia, which occurred occasionally and without a clear relationship to the applied dose, and only one patient experienced grade 2 neutropenia at a DL of 189 mg/m2/day. For both schedules, the median time to nadir for absolute granulocyte count was 8 days, with a median resolution by day 13.
Gastrointestinal toxicities
BAY 38-3441 administered as a single infusion for either 30 min or 2 h every 3 weeks did not cause any significant gastrointestinal adverse event across the applied dose levels. On the 3-day schedule, BAY 38-3441 administration caused diarrhea that was mild to moderate until DL 246 mg/m2/day. At 320 mg/m2/day, more than half of the patients (10 of 19) experienced diarrhea, which was generally mild. However, in two out of 19 patients, diarrhea reached grade 3 or 4. After further dose escalation to BAY 38-3441 416 mg/m2/day, four out of seven patients experienced diarrhea and hospitalization was required in one case. The episode of diarrhea usually started on or after day 4 and lasted an average of 3 days.
Nausea and vomiting were generally mild across all dose levels on the single-dose schedule. On the 3-day schedule, two patients experienced grade 3 nausea and vomiting despite routine premedication. In one of these patients, nausea and vomiting were due to Helicobacter pylori-induced gastritis.
Renal toxicity
Grade 2 renal toxicity, i.e. isolated creatinine elevation, was first observed at DL 315 mg/m2/day on the single-dose schedule. Renal toxicity was usually seen on day 2 and was completely reversed within 2 days in all patients. Attempts to reduce renal toxicity with adequate hydration were not successful. Prolongation of the infusion time from 30 min to 2 h at DL 470 mg/m2 attenuated renal toxicity, but did not prevent the occurrence of renal toxicity at BAY 38-3441 600 mg/m2. Although renal toxicity remained mildmoderate until DL 416 mg/m2 on the 3-day schedule, the clinical data suggest a clear relationship between dose level and elevation of serum creatinine. Indeed, all seven patients at DL 416 mg/m2 on the 3-day schedule demonstrated mildmoderate renal toxicity during cycle 1, despite normal renal function for all patients at study entry. Although cumulative toxicity was difficult to assess since the majority of patients received only a total of two courses, renal toxicity did not amplify upon continued drug treatment during cycle 2 without dose modification. Moreover, two patients receiving six or more cycles did not show cumulative renal toxicity or any signs of unexpected late toxicities. Urinalyses did not show any degree of hematuria, casts or elevated protein across the dose levels. Elevation of creatinine was not associated with a change in ultrasonographic appearance of the kidneys in any patient. In addition, any predispositions or determinants for renal toxicity were not detectable. Dose level 320 mg/m2/day on the 3-day schedule was chosen as the RPD for BAY 38-3441, with only one of 19 patients presenting mild elevation of serum creatinine.
Biochemical toxicities
Four patients developed grade 1 isolated hyperbilirubinemia on day 4 that resolved within 48 h. Hyperbilirubinemia was not observed beyond DL 246 mg/m2/day on the 3-day schedule and was not seen in any patients on the single-dose schedule. ALP elevation was reported in only one patient on the single-dose schedule and in four patients on the 3-day schedule. In these four patients, elevation of ALP was not associated with hyperbilirubinemia. In all of the patients, both hyperbilirubinemia and elevation of ALP were reduced or not detected during the second cycle without dose modification.
Responses
Of the 79 patients evaluable for response, two patients on the 3-day schedule had stable disease for 18 and 21 weeks. Both patients entered the trial with evidence of disease progression. One of these patients with advanced colorectal cancer refractory to third-line therapy, including irinotecan, was treated with BAY 38-3441 246 mg/m2/day. The other patient was in the 320 mg/m2/day cohort and had advanced NSCLC refractory to third-line combination therapy. This subject showed stable disease after the seventh cycle, but died from a heart attack due to concomitant coronary heart disease.
Pharmacokinetics
Plasma samples for pharmacokinetic analysis were obtained from 78 patients. The plasma concentrationtime profiles of BAY 38-3441 and total CPT (lactone and carboxylate form) are shown in Figure 2A. For both schedules, the pharmacokinetic parameters of BAY 38-3441 and its cleavage product, CPT, appeared to be dose-dependent, but not linear (Tables 4 and 6; Figure 2). Plasma concentrations of BAY 38-3441 (Figure 2A, ) increased until the end of the 30-min infusion and then decreased in a three-exponential manner, with an apparent terminal half-life of 4.312 h. Median maximum plasma concentrations of CPT were reached between 0.5 and 22 h after the start of the BAY 38-3441 infusion, and most tmax values were in the range of 2.510 h (Tables 4 and 6), suggesting that CPT Cmax values were reached at times when only small concentrations of the parent compound were still present. Thereafter, plateau-like plasma concentrations of CPT were observed for nearly 48 h, followed by a gradual decrease corresponding to an apparent terminal half-life of 1749 h (Figure 2B, ), consistent with what has been previously reported [1, 2
, 12
]. There was no obvious association between the occurrence of either renal toxicity or diarrhea and the Cmax of either BAY 38-3441 or CPT. Furthermore, renal toxicity was not dependent on urinary excretion of BAY 38-341 or CPT for either the 30-min infusion (Tables 4 and 6) or the 2-h infusion (Table 5).
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Discussion |
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Topotecan has increased aqueous solubility and lactone ring stability, with 22% of the compound remaining in the lactone form at equilibrium in human blood [24]. Myelosuppression is the major DLT for topotecan, and the drug is delivered intravenously as a 30-min daily infusion for several consecutive days [12
]. Irinotecan is a pro-drug with limited activity. In plasma, it is converted into the active metabolite SN-38 [30
]. Like topotecan, irinotecan has increased water solubility over CPT and is administered as an intravenous infusion. At equilibrium in human whole blood, 21% is in the active lactone form [24
]. DLTs include leukopenia, neutropenia and diarrhea in the single-dose regimens, and primarily gastrointestinal toxicity with the continuous infusion schedules [31
, 32
]. Because of the pronounced gastrointestinal toxicity, it has been difficult to combine irinotecan with other cytotoxic agents.
BAY 38-3441 was tested for stabilization of the lactone ring in comparison with topotecan in an aqueous solution containing two molar equivalents of sodium hydroxide. In these studies, <2% of the lactone ring of BAY 38-3441 was converted to the inactive carboxylate form, compared with 94% inactivation of the lactone ring of topotecan [28].
In the present phase I study, BAY 38-3441 was administered as a daily infusion once every 3 weeks (single-dose schedule) or once daily for three consecutive days every 3 weeks (3-day schedule). On a single-dose schedule, renal toxicity was dose-limiting and appeared at doses 470 mg/m2 when the study drug was infused for 30-min. When the infusion time was extended to 2 h, renal toxicity was dose-limiting at BAY 38-3441 600 mg/m2, increasing the MTD from 315 to 470 mg/m2 for the single-dose schedule. Renal toxicity was also observed in patients on the 3-day schedule at the 416 mg/m2/day DL. On this schedule, at the 320 mg/m2/day DL, only one of 19 patients developed mild elevation of serum creatinine. However, although grade 2 renal toxicity was not a DLT in this study, it may present a potential problem in clinical practice.
Although dose-limiting neutropenia (not complicated by neutropenic fever in this study), thrombocytopenia and diarrhea were observed at the higher dose levels, renal toxicity was the principal and most serious DLT. This finding was unexpected because BAY 38-3441 is predominantly excreted via the biliary/fecal route in all species studied in the preclinical program (rat, dog and mouse). In addition, subacute administration of BAY 38-3441 to dogs and rats resulted in renal changes that were dose-related, but not dose-limiting in the animals examined. Therefore, the mechanism of renal toxicity in patients here remains unclear. Although the molecular weight of BAY 38-3441 is above glomerular filtration, approximately 26% of the BAY 38-3441 dose (see Tables 46) is detectable in the urine, most likely due to tubular secretion. However, elevation of creatinine was not dependent on the BAY 38-3441 concentration in the urine or urine pH. In addition, there were no crystals of CPT in the urine of the patients.
Recently, Rowinsky et al. reported a phase I and pharmacokinetic study of pegylated CPT (PEG-CPT) as a 1-h infusion every 3 weeks in patients with advanced solid malignancies [33]. Similar to the peptide-carbohydrate moiety of BAY 38-3441, the PEG-CPT prodrug stabilizes the CPT in its active lactone configuration [34
], and selective tumor distribution may also occur as a result of the molecular weight and physicochemical properties of PEG-CPT [35
]. Neutropenia was the principal DLT of PEG-CPT, and severe anemia and thrombocytopenia were occasionally associated with neutropenia. A total of two out of 37 patients developed transient grade 12 elevations in serum creatinine concomitant with genitourinary toxicity. Hence, it is possible that the renal toxicity observed in our phase I study is related to the glycoconjugated CPT prodrug rather than to the CPT plasma concentration profiles.
Schoemaker et al. performed a phase I study using camptothecin linked to a water-soluble polymeric backbone (MAG-CPT) [36] and administrated as a 30-min infusion over three consecutive days every 4 weeks to patients with malignant tumors. Hematological toxicity was relatively mild, but serious bladder toxicity was encountered which was found to be dose-limiting [36
]. Comparing these camptothecin conjugates, MAG-CPT showed a substantially higher AUC and longer half-life compared with BAY 38-3441 (t1/2 3.911.3 days compared with 7.054 h, respectively). Furthermore, with MAG-CPT the kinetics of free camptothecin were release-rate dependent (t1/2 5.817.5 days) [36
]. In contrast, peak plasma concentrations and AUC of BAY 38-3441 and CPT were dose-dependent, but not linear, for both schedules, and plateau-like CPT plasma concentrations were observed for nearly 48 h followed by a gradual decrease corresponding to an apparent terminal half-life of 1749 h. The pharmacokinetic data also demonstrate that there is no significant difference in the BAY 38-3441 plasma concentration profiles [Cmax and AUC(024 h)] between the single dosing and daily dosing for 3-day schedules at the 315 (320) and 416 (470) mg/m2 dose levels (see Tables 4 and 6). These findings are consistent with the results obtained in the rat and dog models. This observation is due to BAY 38-3441 being rapidly cleared from the central compartment after intravenous administration with no significant drug accumulation upon multiple dosing for 3 days. This is in contrast to the dramatically changed kinetics of camptothecin with MAG-CPT [36
], showing prolonged exposure and cumulative bladder toxicity, which is typical for camptothecin.
In this study, bladder toxicity was not detectable clinically or by urinalysis. However, diarrhea was recorded in several patients and was more evident in patients on the 3-day schedule. For example, at DL 416 mg/m2/day on the 3-day schedule, diarrhea was reported in four of six patients and was dose-limiting in one of these patients. The incidence of diarrhea was similar to the delayed-onset diarrhea induced by irinotecan [12, 31
, 32
] and typically appeared on day 5 with a median duration of 5 days. Three out of 19 patients on the 3-day schedule experienced diarrhea at the RPD, with only one patient requiring hospitalization. The mechanism of BAY 38-3441-associated diarrhea has not been fully defined. Dogs treated with BAY 38-3441 exhibited intestine glandular necrosis that was observed at 26 mg/kg and 60 mg/kg. Although the liver and gastrointestinal tract were the target organs for tissue distribution in animal models, BAY 38-3441 does not appear to undergo significant metabolism.
Because of the improved safety profile and pharmacokinetics for both BAY 38-3441 and CPT, the 3-day schedule was preferred over the single-day schedule. Thus, the RPD is BAY 38-3441 320 mg/m2/day administered as a 30-min infusion on the 3-day schedule. Major responses were not observed during this phase I study, possibly because the majority of patients were extensively pre-treated and almost all patients with gastrointestinal cancer were refractory to irinotecan before study entry.
Received for publication December 12, 2003. Revision received March 31, 2004. Accepted for publication April 7, 2004.
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