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© 2003 American Society for Clinical Oncology A Phase I and Pharmacokinetic Study of Pegylated Camptothecin as a 1-Hour Infusion Every 3 Weeks in Patients With Advanced Solid Malignancies
From the Institute for Drug Development, Cancer Therapy, and Research Center; The University of Texas Health Science Center at San Antonio; Brooke Army Medical Center, San Antonio, TX; and Enzon Inc., Piscataway, NJ. Address reprint requests to Eric K. Rowinsky, Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX; email: erowinsk{at}saci.org.
Purpose: To assess the feasibility of administering camptothecin (CPT), the prototypic topoisomerase I inhibitor, as polyethylene glycol (PEG)-CPT, a macromolecule consisting of CPT conjugated to chemically modified PEG. The study also sought to determine the maximum-tolerated dose (MTD) of PEG-CPT, characterize its pharmacokinetic behavior, and seek preliminary evidence of anticancer activity. Patients and Methods: Patients with advanced solid malignancies were treated with escalating doses of PEG-CPT as a 1-hour intravenous (IV) infusion every 3 weeks. A modified continual reassessment method was used for dose-level assignment to determine the MTD, which was defined as the highest dose level at which the incidence of dose-limiting toxicity did not exceed 20%. Results: Thirty-seven patients were treated with 144 courses of PEG-CPT at seven dose levels ranging from 600 to 8,750 mg/m2. Severe myelosuppression was consistently experienced by heavily pretreated (HP) and minimally pretreated (MP) patients at the highest dose level evaluated, 8,750 mg/m2, whereas both HP and MP patients tolerated repetitive treatment at 7,000 mg/m2. Cystitis, nausea, vomiting, and diarrhea were also observed but were rarely severe. A partial response was noted in a patient with platinum- and etoposide-resistant small-cell lung carcinoma, and minor responses were noted in one patient each with adenocarcinoma of unknown primary type and osteosarcoma. The pharmacokinetics of free CPT were dose proportional. Free CPT accumulated slowly in plasma, with maximal plasma concentrations achieved at 23 ± 12.3 hours; the harmonic mean half-life (t1/2) of free CPT was long (t1/2, 77.46 ± 36.77 hours). Conclusion: Clinically relevant doses of CPT can be delivered by administering PEG-CPT. The recommended dose for phase II studies in both MP and HP patients is 7,000 mg/m2 as 1-hour IV every 3 weeks. The characteristics of the myelosuppressive effects of PEG-CPT, the paucity of severe nonhematologic toxicities with repetitive treatment, the preliminary antitumor activity noted, and the slow clearance of CPT enabling simulation of desirable pharmacokinetic parameters with a convenient single-dosing regimen warrant further disease-directed evaluations.
AN EXTENSIVE NATIONAL Cancer Institute program to screen natural products in the 1950s led to the isolation of an extract of the Chinese tree Camptotheca acuminata, which demonstrated impressive cytotoxic activity against a wide range of murine and human leukemias and solid malignancies as well as a lack of cross-resistance with available agents.1,2 In 1966, Wall et al1 demonstrated that camptothecin (CPT; Fig 1  ) was the active constituent of the extract.1 CPT was markedly schedule-dependent, with more frequent treatment generally producing greater cytotoxicity than less frequent schedules.1,2 Because of the aqueous insolubility of the active, closed-ring lactone form of CPT, it was formulated for early clinical trials as a ring-opened sodium salt, which was active only by virtue of ring closure that preferentially occurred in an acidic pH range.2 Anticancer activity was noted in patients with colorectal, gastric, small bowel, non–small-cell lung carcinomas, and malignant melanoma in phase I and limited phase II studies.2–8 However, high rates of severe and unpredictable hemorrhagic cystitis and gastritis, which in retrospect were caused by lactone ring closure and direct mucosal toxicity in acidic urothelial and gastric tissues, led to suspension of CPT’s development for several decades.3–8
Whereas early studies indicated that CPT inhibits DNA, RNA, and protein synthesis, its precise mechanism of action was not known for several decades.9–12 Recognition that CPT stabilized covalent adducts between DNA and the topoisomerase I (topo I) inhibitor renewed interest in developing CPT analogs 20 years later. The CPT analogs that have undergone clinical development differ substantially in their anticancer spectra and in their toxicological, pharmaceutical, and pharmacological profiles.2,13 Whereas the clinical roles for these agents have been well established, the overall therapeutic impact of available CPT analogs has been modest, and many approaches to optimize their therapeutic indices are being evaluated.13,14 This reasoning has served as the rationale to re-evaluate strategies to feasibly administer CPT. One strategy involves conjugating CPT to a chemically modified polyethylene glycol (PEG) macromolecule.15–21 The highly water soluble and stable prodrug pegylated-CPT (PEG-CPT; Prothecan, Enzon, Piscataway, NY; Fig 1  ), synthesized by conjugating PEG to the 20-hydroxyl group of CPT, undergoes enzymatic hydrolysis that releases CPT in tissues and biologic fluids.14–19 An advantage of this approach may be that the acylated CPT prodrug locks the CPT E ring in its desired active lactone configuration.21,22 Selective tumor distribution may also occur as a result of the high molecular weight and specific physicochemical properties of PEG-CPT, which potentially results in enhanced vascular permeation and intrasomal retention.23,24 Furthermore, PEG-CPT demonstrated impressive and broad activity against human tumor xenografts of colon, lung, breast, and pancreatic origin, and its efficacy was superior to those of topotecan and irinotecan in many models.23,24 In rodents and dogs, hematopoietic, gastrointestinal, and lymphoid tissues were most prone to the toxicities of PEG-CPT, and noncumulative myelosuppression was the principal dose-limiting effect on both single- and divided-dose regimens.25 The results of the aforementioned studies indicate that PEG-CPT may be a feasible means to administer CPT, in contrast to earlier efforts using high doses of the sodium salt. The principal objectives of this study were to (1) determine the maximum-tolerated dose (MTD) of PEG-CPT administered as a 1-hour IV infusion every 3 weeks and recommend doses for phase II trials, (2) characterize its toxicities, (3) describe the pharmacology of PEG-CPT, and (4) seek preliminary evidence for antitumor activity.
Patient Selection Patients with solid malignancies who failed to respond to standard therapy or for whom adequate therapy was not available were eligible for this study. The following eligibility criteria were also included: age of 18 years or older; an Eastern Cooperative Oncology Group (ECOG) performance status  2; no prior chemotherapy, investigational agents, or wide-field radiation therapy within 4 weeks (6 weeks for nitrosourea and mitomycin); adequate hematopoietic (absolute neutrophil count [ANC] 1,500/µL, hemoglobin  8.5 g/dL, platelets 100,000/µL), hepatic (total bilirubin 1.5 mg/dL, transaminase 2.5 times institutional normal upper limit [ 5 times if caused by liver metastasis]), and renal (creatinine 1.5 mg/dL) functions; no enteropathy or recent onset of diarrhea, defined as an excess of two to three stools above the normal rate within 4 weeks; no evidence of microscopic hematuria ( 10 RBCs/high power field), unless caused by a nonurothelial etiology; no active brain metastases; and no coexisting medical problem of sufficient severity to limit compliance with the study. Before treatment, patients gave written informed consent according to federal and institutional guidelines.
Dosage and Drug Administration PEG-CPT was supplied by Enzon (Piscataway, NJ) as a sterile white lyophilized powder in 50-mL amber vials. Each 1 mL of reconstituted drug consisted of 60 mg of PEG-CPT (1.0 mg of CPT) and 9 mg of sodium chloride, USP, in water for injection, USP. The drug was reconstituted by adding 20 mL of 0.9% saline solution, USP, to the vial containing 1.2 grams of PEG-CPT (20 mg CPT). The stock solution was further diluted with 0.9% saline solution, USP, to a total volume of 250 mL.
Pretreatment and Follow-Up Studies
Plasma and Urine Sampling and Assay Before analysis, 500-µL plasma samples were thawed on ice, and 1.0 mL of extraction solvent (4% acetic acid in acetonitrile) was added to precipitate proteins. Samples were mixed and then centrifuged at 3,000 rpm for 10 minutes, and 500 µLs were placed in a polypropylene tube and diluted with 500 µL of 20 mmol/L ammonium acetate buffer, pH 3.0. The mixture was then passed through a 0.45-micron, 13-mm nylon syringe filter. Separation of the plasma samples for quantification of CPT was accomplished by reverse-phase high-performance liquid chromatography (HPLC) and fluorescence detection (wavelengths, 370 nm [excitation] and 420 nm [emission]). Separation of CPT was accomplished using a Phenomenex Jupiter (4.6 x 250 mm, 300A) C18 column protected by a Jupiter (4.6 x 30 mm, 300A) precolumn (Phenomenex, Torrance, CA). The drug of interest was eluted using a linear gradient mobile phase of solvent A (0.02 M ammonium acetate, pH 4.5) and solvent B (0.20% PEG in acetonitrile) at a flow rate of 1.0 mL/min and injection volume of 20 µL. CPT eluted at 11.5 minutes. Standard curves (5 to 1,000 ng/mL) were prepared by adding known amounts of CPT to heparinized human plasma. Using a weighting factor of 1/x, back-calculated curve concentrations were determined by plotting the peak heights of the spiked standards versus their theoretical concentrations. The lower and upper limits of assay quantification were 5 and 1,000 ng/mL, respectively. Assay performance was monitored using quality control (QC) samples prepared at 10.0, 80.0, 231.0, and 924.0 ng/mL. Duplicate QC samples and patient samples were extracted and quantified, and analytic runs were considered acceptable if two thirds of the QC samples were within ± 15% of their theoretical concentrations, and at least one QC sample at each concentration was acceptable. An HPLC assay, designed to quantify the PEG-CPT macromolecule, could not be sufficiently validated, and therefore, only data for free CPT are reported here.
Pharmacokinetic and Pharmacodynamic Analyses The relationships between indices of free CPT (AUC0–72 and Cmax) and myelosuppression were explored. Relevant parameters of myelosuppression that were evaluated included the nadir absolute blood count values and percentage decrements in the ANC and platelet counts. The relationships between the Cmax and AUC0–72 values and hematologic effect were described using the sigmoidal maximal effect model (Emax) drug action, which was fit to the data by nonlinear least-squares regression.30 The coefficient of determination (R2), the standard errors for the estimated parameters, and visual inspection of the fitted plots were used as measures of goodness of fit for the pharmacodynamic model.
General Thirty-seven patients, whose pertinent characteristics are listed in Table 1 , received 144 courses of PEG-CPT at seven dose levels ranging from 600 to 8,750 mg/m2 (Table 2). One course, administered to a patient who developed symptomatic brain metastases shortly after treatment, was not able to be evaluated for toxicity because of its inability to fully comply with the required evaluations. The median number of courses administered was two (range, one to 17). Six patients required dose reduction on one occasion for DLT, whereas the dose of PEG-CPT was reduced twice in two patients. Overall, the mCRM and minimum requirement for a single patient at each dose level had moderate utility. Three of the six dose-escalation increments were maximal (100%), and a single patient was treated at two of the seven PEG-CPT dose levels. Grade 2 neutropenia in the first three patients at 4,800 mg/m2 precluded further dose escalation in increments of 100% as well as further treatment of as few as a single patient at any higher dose level. Because dose-limiting hematologic toxicities that initially seemed to be related to the extent of prior myelotoxic therapy occurred in the first course of several patients treated with PEG-CPT at 5,600 and 7,000 mg/m2, the dose-escalation process diverged thereafter into distinct schemes for MP and HP patients. At 8,750 mg/m2, an unacceptably high rate of DLT was noted, irrespective of the extent of prior therapy, and 7,000 mg/m2 was demonstrated to be the MTD for both HP and MP patients.
Toxicity Hematologic toxicity. Neutropenia was the principal DLT. The ANC nadir typically occurred between days 10 and 15; treatment delays resulting from unresolved neutropenia were uncommon, and there was no evidence of relevant, cumulative effects on blood cell nadirs. The distributions of the grades of neutropenia and thrombocytopenia, as well as hematologic DLTs as a function of dose level, are listed in Table 3 . Scatterplots depicting ANC, platelet nadirs, and the percentage decrements in ANC and platelet counts as functions of the PEG-CPT dose are depicted in Fig 2A–2D. Interindividual variability in all hematologic parameters was large, and there was a high degree of overlap between MP and HP patients. Severe hematologic toxicity was initially noted in an HP patient who experienced grade 4 neutropenia lasting longer than 5 days in a first course at 4,800 mg/m2. Five additional patients were treated at 4,800 mg/m2, all of whom experienced no hematologic DLTs in course 1. Overall, dose-limiting hematologic events occurred in two (9.5%) of 28 courses at 4,800 mg/m2. Of the nine patients who received 34 evaluable courses at the next higher dose, 5,600 mg/m2, two patients developed hematologic DLTs, including grade 4 neutropenia exceeding 5 days in an HP patient (course 1) and grade 4 thrombocytopenia in an MP patient (course 7). Because none of the first three patients treated with PEG-CPT 7,000 mg/m2 experienced DLT, dose escalation proceeded. In contrast, PEG-CPT 8,750 mg/m2 produced an unacceptably high rate of intolerable toxicity, with two (one MP and one HP patient) of three patients developing dose-limiting neutropenia and severe thrombocytopenia. Further experience demonstrated that 7,000 mg/m2 was well tolerated by both HP and MP patients; hematologic DLT was experienced by one of 13 (7.6%) patients, including six MP and seven HP patients, and occurred in four of 36 (11%) courses. Therefore, 7,000 mg/m2 was considered the MTD, irrespective of the extent of prior myelotoxic therapy.
Severe effects on platelets and RBCs were less common than severe neutropenia. Similar to neutropenia, there was a greater propensity for HP patients to experience thrombocytopenia or anemia of any grade, but the rates of clinically relevant events did not significantly differ between MP and HP patients. Anemia related to PEG-CPT was generally mild (grade 1 [eight courses]) or moderate (grade 2 [seven courses]) and tended to progressively worsen with repetitive treatment. However, grade 3 anemia requiring RBC transfusions was noted in only four (3%) courses involving four (11%) patients. Nonhematologic toxicity. Because sodium CPT resulted in unpredictable and severe gastrointestinal and genitourinary toxicities in early trials, heightened attention was paid to these organ systems. Indeed, nausea and/or vomiting were the most common nonhematologic events in this study. Twenty-four (65%) patients had grade 1 or grade 2 nausea at some time during treatment, whereas 12 (32%) patients developed grade 1 vomiting. Nausea and vomiting generally occurred in the pretreatment period, typically resolved within 24 to 48 hours after treatment, and seemed dose related. Delayed toxicity was not noted. These toxicities were also prevented and/or managed successfully with prochlorperazine or serotonin 5HT3 antagonists, but routine premedication was not required because most events consisted of nausea alone and were sporadic, brief, and mild. Thirteen (35%) patients, most of whom had colorectal carcinoma that had been previously treated with fluorpyrimidine- or irinotecan-based therapies, developed diarrhea at some time during treatment. Except for one isolated episode of brief, grade 3 diarrhea, all events were mild or moderate. The patient, a 46-year-old male HP with non–small-cell lung carcinoma who had previously received five courses of PEG-CPT at 5,600 mg/m2 without DLT, developed grade 3 diarrhea associated with neutropenia (grade 4) and thrombocytopenia (grade 3) in his sixth course; negligible toxicity ensued during four additional courses at 4,800 mg/m2. Manifestations of genitourinary toxicity, including hematuria, dysuria, bladder spasm, nocturia, and increased urinary frequency were experienced by 13 (35%) patients. All affected patinets were initially treated with PEG-CPT doses ranging from 4,800 to 7,000 mg/m2. Whereas genitourinary effects were generally noted after treatment with multiple courses of PEG-CPT, they were always self-limited, and toxicity did not worsen progressively in patients who received further treatment. However, two patients experienced grade 3 toxicity. The first patient, a 56-year-old male with abdominal carcinomatosis, developed gross hematuria and dysuria and increased urinary frequency after receiving three courses of PEG-CPT at the 4,800 mg/m2 dose level. The gross hematuria and dysuria resolved before the scheduled date of retreatment. Urinalysis, ultrasonography, and chemistries did not indicate a primary renal etiology. Because this event met the criteria for DLT, three additional courses of PEG-CPT were administered at a reduced dose, 2,400 mg/m2, which was associated with intermittent microscopic hematuria (grade 1). The second patient with grade 3 genitourinary toxicity, a 70-year-old male with an advanced pancreatic islet cell carcinoma, developed dysuria, nocturia, and intermittent, brief gross hematuria during his fifth course of PEG-CPT at 5,600 mg/m2, which had been reduced because of hematologic DLT during a fourth course at the 7,000 mg/m2 dose level. Cystoscopic examination revealed diffuse inflammation of the urothelial mucosa, which was confirmed pathologically. All clinical manifestations, as well as microscopic hematuria, resolved within 8 weeks. Two patients developed transient grade 1 to 2 elevations in serum creatinine concomitant with genitourinary toxicity, albeit in the face of progressive malignant disease. Nine patients also experienced isolated, sporadic, and minimal (grade 1) complaints or laboratory abnormalities indicative of genitourinary toxicity, including hematuria (four patients), bladder spasms (one patient), nocturia (one patient), increased urinary frequency (one patient), and dysuria (two patients); however, all of these affected patients received additional treatment with PEG-CPT without further genitourinary manifestations. These patients had no readily identifiable common determinants and no potential risk factors for genitourinary toxicity, such as sex, age, history of genitourinary problems, human serum albumin concentration, medications, and outlying pharmacokinetic and drug excretion profiles. Similarly, the ranges of urinary pH values in patients who did and did not experience genitourinary toxicity were nearly identical. A 48-year-old female with metastatic colorectal carcinoma and no history of atopy or hypersensitivity phenomena experienced a major hypersensitivity reaction (grade 3) consisting of diaphoresis, dyspnea, chest discomfort, flushing, and warmth within 2 minutes after the initiation of PEG-CPT treatment at 5,600 mg/m2. These manifestations partially resolved soon after the infusion was discontinued and before treatment with diphenydramine 50 mg IV; complete resolution was evident within 30 minutes. Twenty-four hours after the event, the patient was rechallenged successfully with the same dose of PEG-CPT administered initially at one sixth of the planned rate, and she received a second course 3 weeks later. Premedication, consisting of diphenhydramine 50 mg IV and cimetidine 300 mg IV 30 minutes before treatment and dexamethasone 20 mg orally at 6 and 12 hours before treatment, was administered on these occasions. Alopecia that seemed to be cumulative and dose related was experienced by 14 patients. Other mild to moderate (grade 1 or 2) complaints that were possibly drug related included malaise, weakness, dizziness, and anorexia. These complaints were noted across the entire dosing range, and definite temporal relationships could not be discerned, indicating that the underlying malignant process may have been contributory.
Antineoplastic Activity
Pharmacokinetics and Pharmacodynamics
To assess dose proportionality, Cmax and AUC0–72 values were determined, and both parameters increased proportionately with increasing dose (R2 = 0.55 and 0.62, respectively; Fig 3A , 3B); the 95% CI for the slope of log (AUC0–72) versus log plot (dose level) encompassed a value of 1 (95% CI, 0.7484 to 1.101), which was consistent with dose proportionality. Similarly, the 95% CI for the slope of the log (Cmax) versus log relationship (dose level) ranged from 0.7598 to 1.085, indicating that Cmax also increased in a dose-proportional manner. These observations indicate that the pharmacokinetics of the generation of free CPT in plasma are linear in the PEG-CPT dose range of 600 to 8,750 mg/m2. Interpatient variability at any given dose level was moderate; the coefficient of variation of the extrapolated AUC at 7,000 mg/m2 was 55%. Plasma concentration-time curves for free CPT for patients treated at 7,000 mg/m2 are shown in Fig 4. The fractional urinary excretion of free CPT in 48 hours was low, averaging 1.29% ± 0.67% (n = 36) of the total dose of CPT administered.
Scatterplots depicting the percentage decrements in ANC and platelet counts as functions of AUC0–72 and Cmax values for free CPT are shown in Fig 5A –D. Parameter relationships were described poorly by linear and sigmoidal Emax models (R2 = 0.10 for neutrophils; R2 = 0.20 for platelets). Within any particular dose level, pharmacokinetic parameters reflecting exposure to free CPT were generally greater in those patients who experienced dose-limiting myelosuppression in course 1, but the relatively small numbers of both DLTs and patients at each dose level limited the statistical power of these analyses. Relationships between the other main adverse effect of PEG-CPT and indices reflecting drug exposure (Cmax and AUC0–72) were sought. No differences were evident between patients who did (n = 13) and did not (n = 24) experience any genitourinary toxicity or in the two patients who developed grade 3 toxicity (P > 0.4 for all comparisons). Similarly, the fractional excretion of free CPT over 48 hours was similar in these three groups (P > .4 for all comparisons).
CPT was selected as a candidate for pegylation and clinical development because of its impressive and broad activity against human tumors, particularly xenografts resistant to common anticancer agents, which is generally superior to those of topotecan and irinotecan.1,2,9–14 One explanation for this lack of cross-resistance may be that CPT, unlike many CPT analogs, is not a substrate for multidrug transporters and retains activity against tumors with acquired multidrug resistance conferred by P-glycoprotein overexpression.31–35 The pegylation technology, in which agents are conjugated to chemically modified PEG, can favorably alter the pharmaceutic, pharmacologic, and immunologic properties of small or organic molecules, proteins, enzymes, oligonucleotides, and liposomes, ultimately increasing their utility.15–18 In oncology and related disciplines, pegylation has added value to many therapeutics, including L-asparaginase, interferon, and essential enzymes for immunodeficiency disorders.15 Indeed, PEG-CPT, which is much more water soluble than CPT, has demonstrated feasibility from a pharmaceutical standpoint and impressive antitumor activity in preclinical studies.23,24 Furthermore, the synthesis of PEG-CPT, in which PEG is conjugated to CPT at the 20-OH position, which essentially "blocks" this position, thereby creating an "inert" prodrug before hydrolytic release of CPT.17–19 Indirect evidence indicates that CPT is locked into its active lactone configuration as a component of the acylated PEG-CPT prodrug.21,22 It is also reasonable that the active CPT lactone may predominate over the inactive ring-opened species in the acidic milieu of tumors, thereby enhancing the tumor selectivity of PEG-CPT. Another potential advantage of pegylated macromolecules is that they may passively accumulate in tumors because of the phenomenon of enhanced vascular permeation and intrasomal retention.23,24 Finally, prodrugs engineered to slowly release cytotoxic "payloads" may more readily simulate optimal pharmacologic profiles compared with the payload alone, particularly in situations in which protracted drug exposure is desired. The cumulative results of preclinical studies with topo I–targeting agents indicate that cytotoxicity is maximal on more divided and continuous schedules, which has served, in part, as the rationale for developing PEG-CPT.1,2,13 As predicted from preclinical studies, neutropenia was the principal DLT of PEG-CPT, and severe anemia and thrombocytopenia were occasionally associated with severe neutropenia. Whereas grade 3 and 4 neutropenia were common at the PEG-CPT dose level of 7,000 mg/m2, the duration of severe neutropenia was generally brief, and dose-limiting myelosuppression was uncommon. At 7,000 mg/m2, the incidence of hematologic DLT was acceptable, occurring in one (7.7%) of 13 patients in course 1 and in three (8.3%) of 36 total courses. However, an unacceptably high rate of dose-limiting hematologic events was noted at the next higher dose (8,750 mg/m2). Whereas hematologic effects were generally more severe in HP patients at any given dose and level of drug exposure, these differences were not clinically significant as the relative rates of DLT were similar. The early onset and resolution of cytopenias, the low rate of severe myelosuppression requiring treatment delay, and the lack of cumulative hematologic toxicity indicate that immature hematopoietic precursors are relatively unaffected by PEG-CPT, and 7,000 mg/m2 is an appropriate starting dose for both MP and HP patients with good performance status and organ function. The attention paid to genitourinary and gastrointestinal systems was heightened from the outset because of the early experience with sodium CPT. All gastrointestinal toxicities were mild or moderate in severity, and neither routine premedication with antiemetics nor complex schemes to manage diarrhea were required.13 Manifestations indicative of cystitis occurred in 13 (35%) of 37 patients; however, most events were mild and principally consisted of isolated microscopic hematuria. Furthermore, most affected patients were retreated with PEG-CPT, without recurrence or worsening of toxicity. Nonetheless, there is still cause for concern, as two patients did experience grade 3 toxicity, but the duration of severe manifestations was brief, and repetitive treatment at a lower dose was well tolerated. Whereas information about the tolerance of repetitive treatment is limited, six patients tolerated at least four courses of PEG-CPT at doses ranging from 5,600 to 7,000 mg/m2. In the future, it would seem prudent to evaluate the utility of prophylactic measures in periods of active urinary CPT excretion when the urothelium is most susceptible, such as aggressive oral hydration or bicarbonate administration, to increase urine pH and enhance hydrolysis of the active CPT lactone. Demographic, clinical, and pharmacologic determinants of genitourinary toxicity were not evident in our study, but prospective evaluations in larger numbers of patients will likely be more productive in identifying which patients are appropriate candidates for preventive measures. Whereas the results of fractional urinary excretion studies in the 48-hour posttreatment period were similar in patients with and without genitourinary toxicity, urine collections did not span the entire period in which urinary CPT concentrations were potentially toxic. In early studies of sodium CPT, the median urinary excretion of CPT was 17.6%, indicating that a 48-hour collection period is insufficient to quantify the urinary excretion of CPT after treatment with PEG-CPT. The plasma kinetics of free CPT released from PEG-CPT are complex, reflecting an interplay between release of CPT from PEG-CPT and clearance of both PEG-CPT and CPT. Cmax values were achieved at 23 ± 12.3 hours posttreatment, and the harmonic mean t1/2 was 77.46 ± 36.77 hours, which is substantially longer than comparable values reported for irinotecan, SN-38, topotecan, 9-nitroCPT, 9-aminoCPT, and exatecan.2,13 In early reports describing the pharmacokinetics of CPT after administration of sodium CPT as a brief infusion, t1/2 values were also lower, ranging from 13 to 66 hours (median, 22 hours).34 At the MTD in our study, Cmax values ranged from 292 to 1,014 ng/mL (mean, 551 ± 179.1 ng/mL) and free CPT concentrations at 5 days posttreatment averaged 128.5 ± 107.4 ng/mL, which was in the lower end of the range of minimum plasma CPT concentrations (Cmin, 170 to 1,290 ng/mL) achieved during five daily IV infusions of sodium CPT in an early study.5 In that study, patients who developed severe toxicity generally had higher Cmin values, but pharmacodynamic relationships could not be modeled satisfactorily. Furthermore, toxicity could not be related to either serum albumin, serum protein, or treatment with highly protein-bound drugs. Whereas maintenance of potentially cytotoxic plasma CPT concentrations for protracted periods may seem worrisome from a toxicologic standpoint, Cmax values in studies of sodium CPT were 100- to 200-fold higher than those sustained for several days after treatment with PEG-CPT.3 It follows that differences in the magnitude of CPT Cmax values achieved with sodium CPT and PEG-CPT may account for differences in tolerability. The lack of a feasible analytic assay for the CPT lactone precluded an in-depth study of the kinetics of lactone ring opening after release of CPT from PEG-CPT. However, the cumulative results of pharmacologic studies of most CPT analogs, in which parallel measurements of both total drug and lactone were performed, indicate that the pharmacokinetics and pharmacodynamics of the lactone and total drug are similar.1,13 The results of ex vivo studies indicate that the physiologic pH strongly favors hydrolysis of the CPT lactone ring and that the plasma AUC of the lactone makes up less than 10% of the total AUC.35,36 In essence, the satisfactory modeling of drug effects using total drug concentration data indicates that the open-ring species, albeit inherently inactive, serves as a pH-dependent reservoir for the active lactone. However, neither linear nor sigmoidal Emax models could satisfactorily relate neutropenia to parameters reflecting total free CPT exposure. The inability to relate drug effects to either CPT exposure or PEG-CPT dose may be caused by large interindividual variability in the kinetics of lactone ring opening, which seems to be far greater than that for other CPT analogs. The results of this study indicate that PEG-CPT is a feasible vehicle for administering the prototypical topo I inhibitor CPT. Whereas the main objective of conjugating CPT to a chemically modified PEG is to increase the aqueous solubility and overall feasibility of CPT from a pharmaceutical standpoint, PEG-CPT possesses other desirable properties that result in tolerability at doses associated with antitumor activity. In addition, a single treatment with PEG-CPT results in substantially lower, albeit biologically relevant and protracted, Cmax values than do those achieved with sodium CPT, which may in part explain their widely disparate safety profiles. Furthermore, biologically relevant plasma CPT concentrations were sustained for several weeks, perhaps simulating pharmacologic conditions required for optimal antitumor activity in preclinical studies. Nonetheless, the ultimate clinical activity of PEG-CPT will be defined in appropriate disease-directed clinical trials, but its specific pattern of myelotoxicity, relative paucity of significant nonhematologic toxicity, early evidence of clinical benefit, and the unique preclinical antitumor profile of CPT warrant disease-directed evaluations that are in progress.
Presented in part at the Thirty-Sixth Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, May 15–18, 2000.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
), and the accuracy of the AUC0–
could not be accurately determined for these individuals. Mean Tmax, Cmax, apparent terminal elimination t1/2, and AUC0–
