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© 2000 American Society for Clinical Oncology DX-8951f, a Hexacyclic Camptothecin Analog, on a Daily-Times-Five Schedule: A Phase I and Pharmacokinetic Study in Patients With Advanced Solid MalignanciesFrom the Institute for Drug Development, Cancer Therapy and Research Center; The University of Texas Health Science Center at San Antonio; and Brooke Army Medical Center, San Antonio; Joe Arrington Cancer Center, Lubbock, TX; and Daiichi Pharmaceutical Corporation, Montvale, NJ. Address reprint requests to Eric K. Rowinsky, MD, Institute for Drug Development, Cancer Therapy and Research Center, 8122 Datapoint Dr, Suite 700, San Antonio, TX, 78229; email erowinsk{at}saci.org
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/m2/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/m2/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/m2/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.
THE LARGE DIFFERENCES in the potencies of the camptothecin analogs against topoisomerase I, antitumor spectra, toxicity profiles, and pharmaceutical and pharmacologic properties indicate that further drug discovery and developmental efforts directed at optimizing the overall therapeutic index of this important class of anticancer agents are warranted.1-3 The rationale for synthesizing the hexacyclic camptothecin derivative DX-8951f ([1S, 9S]-1-amino-9-ethyl-5-fluoro-1, 2, 3, 9, 12, 15-hexahydro-9- hydroxy-4-methyl-10H, 13H-benzo [de]-pyrano[3',4':6,7]-indolizino[1,2-b]quinoline-10, 13-dione monomethane sulfonate [salt], dihydrate; exatecan mesylate; Daiichi Pharmaceutical Co, Ltd, Tokyo, Japan; Fig 1) was to exploit physicochemical features anticipated to yield an increased therapeutic advantage compared with other camptothecin analogs.4-8
DX-8951f is water-soluble and does not require enzymatic activation, which may accentuate the fundamentally large interindividual variability in the pharmacologic behavior of the camptothecin analogs and, consequently, in their antitumor and toxicologic profiles.1-3,9,10 DX-8951f is a more potent inhibitor of topoisomerase I than camptothecin, topotecan, and 10-hydroxy-7-ethylcamptothecin (SN-38), the active metabolite of irinotecan.4,6,8 DX-8951f is three- and 10-fold more potent than SN-38 and topotecan, respectively, at inhibiting topoisomerase I extracted from murine P388 leukemia cells, with reported IC50 (concentration that inhibits 50%) values of 0.975, 2.71, 9.52, and 23.5 µg/mL for DX-8951f, SN-38, topotecan, and camptothecin, respectively.4 Furthermore, in a study of the relative antitumor properties of the camptothecin analogs against a panel of 32 cell lines derived from human breast, gastric, colon, ovarian, cervical, lung, and hematopoietic neoplasms, the IC50 values of DX-8951f averaged six- and 28-fold lower than SN-38 and topotecan, respectively.4 In the human tumor cloning assay, DX-8951f also inhibited the growth of clonogenic cells derived from patients with head and neck, non–small-cell lung, liver, lung, breast, colon, ovary, and prostate carcinomas in a dose-dependent manner, and DX-8951f and topotecan were not completely cross-resistant.11 DX-8951f demonstrated impressive and broad activity against human tumor xenografts of colon, lung, breast, renal, and gastric origin, and its efficacy was generally superior to those of topotecan, irinotecan, and 7-(4-methylpiperazinomethylene)-10,11-ethylenedioxy-20[S]-camptothecin dihydrochloride (GI147211).4,8 Although DX-8951f produced impressive activity on both single- and multiple-dosing schedules, superior efficacy against human tumor xenografts was generally noted when the agent was administered on multiple-dosing schedules.4,8 The impressive preclinical antitumor spectra of DX-8951f may, in part, be due to the fact that the agent is not a substrate for the P-glycoprotein multidrug transporter, in contrast to topotecan, 9-aminocamptothecin, and SN-38, which are weak substrates for the efflux pump.12-15 The lack of cross-resistance of P-glycoprotein–overexpressing neoplasms to DX-8951f is indicated by the results of a study in which the agent exhibited similar antitumor activity against human lung cancer PC-6 and its multidrug-resistant P-glycoprotein–overexpressing variant, PC-6/vincristine.5 Similarly, DX-8951f had roughly equivalent potencies against PC-6 and an SN-38–resistant subline characterized by impaired SN-38 accumulation without P-glycoprotein overexpression, and the antitumor activities of DX-8951f were similar against human pancreatic cancers SUIT-2 and KP-1N and their respective sublines that had acquired resistance to CPT-11 in vivo and SN-38 in vitro, presumably due to reduced levels of topoisomerase I mRNA and protein.7 The toxicologic and pharmacologic profiles of DX-8951f have been evaluated in mice, rats, and dogs.16 Rapidly proliferative tissues, including hematopoietic, gastrointestinal, lymph nodal, and reproductive tissues, have been most prone to the toxic effects of DX-8951f, and noncumulative myelosuppression has been the principal dose-limiting effect of DX-8951f on both single- and multiple-dosing regimens in both rodents and dogs. Similar to other camptothecin analogs, there has been considerable interspecies differences in drug tolerance, with dogs being more susceptible to toxicity than rodents. In preclinical pharmacology studies in dogs and rodents using 14C-DX-8951f and high-performance liquid chromatography (HPLC) for differential quantification of lactone and total drug, the half-life (t1/2) of the lactone ranged from approximately 20 to 30 minutes, and systemic exposure to the lactone was approximately 50% of total drug exposure.16 In rats treated with a single intravenous dose of 14C-DX-8951f, urine and fecal recovery averaged 15% and 78% of the administered dose, respectively.16 Hydroxylated metabolites predominated after coincubation of DX-8951f and human liver microsomes ex vivo, and the rate of metabolite formation was decreased by inhibitors of CYP3A.16 DX-8951f was also shown to be highly bound to plasma proteins in both rats (> 90% at 5 minutes) and dogs (> 80% at 5 minutes), and spectrometric studies indicated that the lactone is selectively stabilized by albumin under physiologic conditions.16 The results of the aforementioned studies suggest that DX-8951f may have a superior therapeutic index compared with that of other camptothecin analogs. The principal objectives of this study were to (1) determine the maximum-tolerated dose (MTD) of DX-8951f administered as a 30-minute intravenous infusion daily for 5 days repeated every 3 weeks in both minimally pretreated (MP) and heavily pretreated (HP) patients, and recommend doses for phase II trials; (2) characterize the toxicities associated with this schedule of administration; (3) describe the pharmacology of the anhydrous form of DX-8951f (DX-8951) administered on this schedule; and (4) seek preliminary evidence for antitumor activity.
Patient Selection Patients with histologically confirmed advanced solid malignancies that failed to respond to standard therapy or for whom adequate therapy was not available were eligible for this study. Eligibility criteria also included age  18 years; a World Health Organization (WHO) performance status  2 (ambulatory and capable of self-care); life expectancy 12 weeks; no prior chemotherapy or wide-field radiation therapy within 4 weeks of treatment (6 weeks for nitrosoureas and mitomycin); adequate hematopoietic (absolute neutrophil count [ANC] 1,500/µL, hemoglobin level 8.5 g/dL, and platelet count 100,000/µL), hepatic (total bilirubin 1.5 mg/dL, AST and ALT 2.5 times institutional upper limit of normal[< five times institutional upper limit of normal for patients with liver metastasis]), and renal (creatinine 2.0 mg/dL) functions; measurable or assessable disease; prothrombin time 1.5 times institutional upper limit of normal; no chronic enteropathy nor recent onset of diarrhea defined as an excess of two to three stools/d above the normal frequency in the past 4 weeks; and no coexisting medical problem of sufficient severity to limit compliance with the study. Because preclinical studies had suggested that DX-8951 is metabolized by CYP3A P450 enzymes, patients were instructed to avoid a list of medications, foods, and beverages that could potentially modulate this enzyme system. These medications, foods, and beverages were discontinued if they were determined to not be absolutely necessary and/or if substitutions were available. All medications were recorded in the case report form. Patients gave written informed consent according to federal and institutional guidelines before treatment.
Dosage and Drug Administration DX-8951f, the methane sulfonic salt of DX8951, was supplied by Daiichi Pharmaceutical Corporation (Montvale, NJ) in vials containing 2 mg of lyophilized drug, calculated as the anhydrous free-base equivalent, 50 or 125 mg of maltose (monohydrate), and a proper quantity of hydrochloric acid (pH 3.3 to 4.7). The drug was diluted in the vial with 0.9% saline solution to obtain a 0.5 mg/mL stock solution. An appropriate volume of the stock solution, to yield the required dose, was further diluted in a polyvinyl chloride infusion bag with 0.9% saline solution to a total volume of 100 mL, which was administered over 30 minutes.
Pretreatment and Follow-Up Studies
Plasma and Urine Sampling and Assay Separation of the plasma samples was accomplished by reverse-phase HPLC after solid-phase extraction. After plasma samples were thawed at room temperature and vortexed, 80 µL of 1 N HCL was added to 500 µL of sample and the solution was vortexed for 3 minutes. Next, 2 mL of a 0.01 mol/L phosphate-buffered solution, pH 7.4, was added to the acidified plasma and the mixture was vortexed for 3 seconds. The samples were then loaded into Mega Elute C-18 1-g cartridges (Varian, Harbor City, CA) that were preconditioned sequentially with 4 mL of methanol and 4 mL of water. After the loaded cartridges were aspirated to dryness and rinsed with 4 mL of water, they were placed into tubes and eluted with 4 mL of a 1 N HCL/methanol mixture (1/99, volume-to-volume ratio [v/v]). Next, 50 µL of an internal standard stock solution, consisting of 200 ng/mL DW-8579 ((1, 9S)-1-amino-9-ethyl-5-fluoro-1, 2, 3, 9, 12, 15-hexahydro-9-hydroxy-10H, 13H-benzo [de]-pyrano[3'4':6,7]-indolizino[1,2-b]quinoline-10, 13-dione hydrochloride) in 82% 0.05 mol/L potassium phosphate buffer, pH 3.00/18% (v/v), was added to the elute, the organic solvent was evaporated under nitrogen, and the final residue was reconstituted with 400 µL, 0.05 mol/L of potassium phosphate buffer, pH 2/acetonitrile (82:18, v/v). The reconstituted solution was then vortexed for 10 seconds, centrifuged through an Ultrafree-MC Centrifugal Filter Unit (Millipore, Bedford, MA), and a 100-µL sample was injected into the HPLC system. The HPLC system was equipped with a TSKgel ODS 80T8, 5-µm, 1.5 x 0.46-cm column (TOSOH, Tokyo, Japan) and a TSKgel ODS 80T8, 5-µm, 1.5 x 0.32-cm guard column (TOSOH). Samples were isocratically eluted with 0.05 mol/L of potassium phosphate buffer, pH 3/acetonitrile (82:18, v/v) at a rate of 1.2 mL/min. The column effluent was monitored fluorometrically using an FL-3000 fluorescence detector (Spectra-Physics, Burnsville, MN), with excitation and emission wavelengths set at 366 nm and 446 nm, respectively. A ChroJet Integrator (Spectra-Physics) and a LABNET (Spectra-Physics) data acquisition system were used, and drug concentrations were determined from linear regression equations derived from calibration curves prepared with known standard samples. Under these conditions, the retention times for DX-8951 and internal standard were 21 and 25 minutes, respectively. The HPLC assay was validated at DX-8951 concentrations between 0.200 and 16.26 ng/mL. The lower limit of reliable detection for DX-8951 was set at the concentration of the lowest nonzero standard, 0.200 ng/mL. The intra-assay coefficient of variation (CV) ranged from 1.6% to 8.9%, whereas the intra-assay accuracy was between 93.6% and 98.5%. Interassay CV values ranged from 1.4% to 14.7%, and the interassay precision was between 95.5% and 108.6%. The analytic procedure used for measuring DX-8951 in urine as well as the precision and accuracy of the procedure were nearly identical to the analytic procedure and quality assurance values established for the plasma assay.
Pharmacokinetic and Pharmacodynamic Analyses
Total DX-8951 plasma concentration data were also analyzed using model-dependent methods. After visual inspection of plasma concentration–time curves, individual data sets were fit with either two- or three-compartment models using nonlinear least-squares regression.20 The goodness of model fit (ie, two- v three-compartment model) was guided by inspection of the weighted sum of squares, dispersion of the residuals, SEs of the fitted pharmacokinetic parameters, and the Akaike information criterion.21 The parameters estimated by the three-compartmental model, which were demonstrated to be systematically superior in fitting all plasma concentrations based on the aforementioned criteria, were then used as prior values for the population pharmacokinetic analysis. The population pharmacokinetic analysis was performed using an iterative two-stage methodology (IT2S).22 All concentrations were modeled using a weighting procedure of Wj + 1/Sj2, where the variance of Sj2 was calculated for each observation using the equation Sj2 = (a + b * Y)2, where a and b are the intercept and slope of each variance model. The slope is the residual variability associated with each concentration (ie, sum of the intraindividual variability and the sum of all experimental errors), and the intercept is related to the limit of detection of the analytic assay. Variance parameter estimates were derived using maximum likelihood analysis (ADAPT-II Release 4; Biomedical Simulations Resource, University of Southern California, Los Angeles, CA).23 These estimates were used as beginning priors and were updated iteratively during the population pharmacokinetic analysis (VARUP, IT2S) until a stable value was found.22 The parameters derived were the macro rate constants
The relationships between indices of DX-8951 exposure (Cmax and AUC) and myelosuppression in the first course were explored. Relevant parameters of myelosuppression that were evaluated included nadir absolute blood count values and percentage decrements in the ANC and platelet counts, which were calculated as follows: 100 x ([pretreatment counts - nadir counts]/pretreatment counts). The relationships between DX-8951 Cmax and AUC and hematologic toxicity were described using the sigmoidal maximal effect (Emax) model of drug action (ie, percentage change in hematologic parameter = Emax x AUC
General Thirty-six patients, whose pertinent characteristics are listed in Table 1, received 130 total courses of DX-8951f at doses ranging from 0.1 to 0.6 mg/m2/d. Twenty-one and 15 patients each were considered MP and HP, respectively. Sixteen patients were previously treated with camptothecin analogs. The total numbers of new patients treated at each dose level, number of assessable courses, and dose escalation scheme are listed in Table 2. The median number of courses administered per patient was three (range, one to 22 courses). Seven patients required dose reductions for severe myelosuppression, and the dose in one subject was inadvertently increased.
Overall, the mCRM and the minimum requirement for a single assessable patient at each dose level had limited utility in this study. After no or negligible drug-related effects were noted in the first courses of the three patients treated at the 0.1 mg/m2/d dose level, the dose of DX-8951f was doubled twice to 0.2 and 0.4 mg/m2/d, but the first patient treated at the 0.4 mg/m2/d dose level experienced hematologic DLT during course 1, precluding further dose escalation in increments of 100%, as well as further treatment of as few as one patient at any dose level. Instead, the mCRM mandated that additional patients be treated at the 0.1 mg/m2/d dose level, but because the DLT was experienced by an HP individual and toxicity was not observed at the 0.2 mg/m2/d dose level, clinical judgment took precedence over the mCRM, resulting in the treatment of additional patients at the 0.4 mg/m2/d dose level. At the 0.4 mg/m2/d dose level, an unacceptably high incidence of DLT occurred in HP patients (two of six) during first courses, whereas no DLT was observed in four MP subjects. Thereafter, the dose escalation process diverged into two distinct schemes for MP and HP patients. The tolerance of lower DX-8951f dose levels, 0.2 and 0.3 mg/m2/d, was evaluated in four and seven HP patients, respectively, and no further DLT was observed. In MP patients, the dose of DX-8951f was increased from 0.4 to 0.6 mg/m2/d, which resulted in an unacceptably high incidence of DLT (two of six patients) during first courses. However, DLT was not observed in six MP patients who were subsequently treated with DX-8951f at an intermediate dose level of 0.5 mg/m2/d. On the basis of these results, the MTD of DX-8951f was determined to be 0.3 and 0.5 mg/m2/d for HP and MP patients, respectively.
Hematologic Toxicity
Severe thrombocytopenia and anemia occurred much less frequently than neutropenia and were usually noted concomitant with severe neutropenia. These effects were also more severe in HP patients, as shown in Fig 2. Grade 4 thrombocytopenia was noted in three of 130 courses of DX-8951f, including two courses (courses 1 and 3) in two HP patients at the 0.4 mg/m2/d dose level and one course (course 8) in one MP patient at the 0.6 mg/m2/d dose level. Anemia related to DX-8951f was generally mild (grade 1) or moderate (grade 2) and cumulative, in that it tended to progressively worsen with repetitive dosing. However, severe (grade 3) anemia, possibly related to drug and requiring RBC transfusions, was noted in 29 courses (22%) involving 16 patients (44%).
Nonhematologic Toxicity Two patients, a 50-year-old male with metastatic colorectal carcinoma and a 74-year-old male with metastatic prostate cancer, died from self-inflicted gunshot wounds on day 16 of course 2 and day 21 of course 1, respectively, at the 0.4 mg/m2/d dose level. After their deaths, the families of both individuals reported that they noted mild to moderate signs and symptoms suggestive of a situational depression that antedated the research study, and both deaths occurred around the Christmas holidays. Several other patients who were treated soon after these events complained of mild emotional liability and insomnia, but, in retrospect, it was felt that the appreciation of these complaints likely represented increased awareness on the part of the research staff with regard to the possibility of drug-related depressive manifestations.
Antitumor Activity
Pharmacokinetic and Pharmacodynamic Studies All 36 patients had complete plasma sampling performed for pharmacokinetic studies of total DX-8951 on day 1, and 16 subjects had complete plasma sampling performed on both days 1 and 5. All individual data sets were analyzed by both noncompartmental and compartmental methods. Representative plasma concentration–time profiles are shown in Fig 3, and mean total DX-8951 pharmacokinetic parameters derived using noncompartmental methods are listed in Table 5. An inspection of the scatterplots of dose versus either Cmax or AUC0-inf for total DX-8951 revealed significant overlap in Cmax and AUC0-inf values within the narrow dose range of 0.1 to 0.6 mg/m2/d (Fig 4). The pharmacokinetics of total DX-8951 on day 1 were characterized by a moderately large Vss averaging 14.36 L/m2 (CV, 30.08%) and a mean elimination t1/2 of 8.75 hours (CV, 48.34%). There were no significant differences (P > .05) between pharmacokinetic parameters derived from paired concentration data sets obtained on days 1 and 5; mean CL values were 1.86 (CV, 56%) and 2.05 (CV, 72%) L/h/m2, respectively.
Because there was no evidence of nonlinear drug elimination, autoinduction, nor inhibition of drug clearance based on visual inspection of individual plasma concentration–time curves, linear pharmacokinetic models were evaluated for quality of fit. A two-compartment model consistently missed peak plasma concentrations and a three-compartment model was systematically superior in fitting all plasma concentration–time data sets for total DX-8951 on both days 1 and 5. Therefore, pharmacokinetic parameters derived from the triexponential model were used to develop a population pharmacokinetic model using an IT2S approach. A representative patient’s plasma concentration data fit to this population model are shown in Fig 5. Pertinent pharmacokinetic parameters for total DX-8951 derived from this model were nearly identical to those derived using noncompartmental methods, with mean CL and  z-t1/2 values of 1.64 L/h/m2 (CV, 57%) and 15.8 hours (CV, 65%), respectively. Mean values for Vc and Vss were 2.40 L/m2 (CV, 40%) and 19.3 L/m2 (CV, 30%), respectively.
Urine was collected continuously for 24 hours after treatment on days 1 and 5 in 26 and 13 patients, respectively. The fractional urinary excretion of total DX-8951 averaged 7.24% (CV, 3.48%) and 12.85% (CV, 48.46%) of the total administered dose on days 1 and 5, respectively. The relationships between both the AUC0-inf and Cmax values for total DX-8951 and the percentage decrements in ANC were best described by sigmoidal Emax models (R2 = 0.34 for both relationships), as shown in Figs 6A and 6B). With these models, the AUC0-inf and Cmax values predicted to yield a 50% decrement in ANC (AUC50 and Cmax-50) were 115 µg ·h/L and 31 µg/L, respectively. The relationships between pertinent pharmacokinetic parameters for total DX-8951 and platelet counts, as depicted in the scatterplots in Figs 6C and 6D, could not be described adequately by linear nor nonlinear models. Within particular dose levels, pharmacokinetic parameters reflecting total DX-8951 exposure were generally greater in those patients who experienced dose-limiting myelosuppression during their first course, but the relatively small numbers of both dose-limiting events and patients at each dose level limited the statistical power of such analyses.
The widely disparate characteristics of the camptothecin analogs, including their potencies at inhibiting topoisomerase I, spectra of antitumor activity, toxicity profiles, and pharmacologic and pharmaceutical properties, suggest that further optimization of the overall therapeutic index of this important class of anticancer agents is possible.1-3 DX-8951f was developed to exploit physicochemical properties that may result in superior antitumor activity, less toxicity and interindividual variability, and greater clinical feasibility than topoisomerase I–targeting agents in clinical use.1-3 The agent was specifically selected for clinical development because of its relatively high potency and impressive activity against a broad range of human tumor cell lines and xenografts, including malignancies that are resistant to other camptothecin analogs and other classes of anticancer agents.4-8 Unlike topotecan, 9-aminocamptothecin, and SN-38, DX-8951f is not a substrate for multidrug transporter P-glycoproteins and retains activity against both tumor cell lines and xenografts with acquired multidrug resistance conferred by P-glycoprotein overexpression.12-15 Another advantage of DX-8951f is that it is an intrinsically active compound and not a prodrug, which reduces concerns about interindividual variability in prodrug activation that could increase the fundamentally large interindividual variability in the toxicologic, pharmacokinetic, and antitumor profiles of the camptothecin analogs.1-3,25-40 Although schedule dependence has not been as prominent with DX-8951f in preclinical studies as with other camptothecin analogs, the cumulative results of these investigations indicate that maximal antitumor activity is achieved with divided dosing schedules, and these observations have served, in part, as the rationale for the present evaluation of DX-8951f on a 30-minute infusion daily for 5 days every 3 weeks schedule.4-8,16 In retrospect, the occurrence of toxicity at only the second dose level, 0.2 mg/m2/d, supports the approach used to select the starting dose, 0.1 mg/m2/d, which is equivalent to one third of the lowest toxic dose in dogs, as well as the methodology used for dose escalation. These dose-finding maneuvers were demonstrated to be both safe and efficient, requiring small numbers of both dose escalation steps and patients before biologic activity was encountered. The starting dose of DX-8951f was eventually determined to be equivalent to 50% of the human toxic dose low and one sixth of the dose associated with an unacceptably high rate of DLT. For the purpose of defining a safe starting dose in humans, albeit a dose that would not be significantly lower than the MTD, extrapolating toxicokinetic data from dogs to humans proved to be useful, and similar dose-selection strategies should also be considered in subsequent phase I studies of DX-8951f and other camptothecin analogs.41 The mCRM was principally used to minimize the number of patients treated at doses significantly lower than the MTD. However, this strategy had limited utility because of similar DX-8951f toxicokinetics in dogs and humans, resulting in the selection of a starting dose that was within a single dose level of the human toxic dose low using dose escalation increments as high as 100%. As predicted from preclinical studies, neutropenia was the principal DLT of DX-8951f in the present study. Although grades 3 and 4 neutropenia were common at DX-8951f doses of 0.3 and 0.5 mg/m2/d in HP and MP patients, respectfully, the duration of severe neutropenia was typically brief, and episodes of severe neutropenia that were prolonged (> 5 days) and/or associated with fever were uncommon. Overall, the rates of DLT in MP and HP patients treated with DX-8951f at the 0.5 and 0.3 mg/m2/d dose levels, respectively, were acceptable. Dose-limiting hematologic events occurred in three of 14 total courses (one during course 1) involving three of seven MP patients at the 0.5 mg/m2/d dose level and none of 14 total courses involving seven HP patients at the 0.3 mg/m2/d dose level. However, further dose escalation in both groups resulted in unacceptably high rates of dose-limiting hematologic events, particularly severe neutropenia. Severe thrombocytopenia and anemia were occasionally noted, especially in HP patients who developed concomitant, severe neutropenia. The early onset and resolution of cytopenias, the low rate of severe hematologic events requiring treatment delay, and the lack of cumulative myelosuppression with repetitive dosing indicate that immature hematopoietic precursors are relatively unaffected by DX-8951f, and that 0.5 and 0.3 mg/m2/d are appropriate starting doses for MP and HP patients, respectively. Nevertheless, treatment with DX-8951f at these doses should be limited to patients with good performance status and organ function similar to those in the present study until patients who are potentially at higher risk for toxicity are studied. Nonhematologic toxicities occurred less frequently than hematologic effects and were rarely severe (grade 3 or 4 events in two [1.5%] of 130 courses). The most common nonhematologic effects were nausea, vomiting, and diarrhea; however, neither the development of antiemetic premedication regimens nor complex schemes to manage and/or prevent diarrhea, similar to the situation with irinotecan, were necessary.1-3,10,34,35,38,39 Of particular interest, DX-8951f was associated with neither clinical nor subclinical manifestations of hemorrhagic cystitis, which, in part, stymied the clinical development of sodium camptothecin and have been noted with 9-nitrocamptothecin.1,3,42 The toxicologic profile demonstrated for DX-8951f to date most closely resembles that of topotecan. However, DX-8951f and topotecan possess different antitumor spectra in preclinical studies and distinct physicochemical properties, most notably those rendering topotecan, and not DX-8951f, a weak substrate for the P-glycoprotein multidrug transporter.4-8,12,15,16 The pharmacokinetic profiles of DX-8951f and topotecan are also similar. The principal pharmacokinetic characteristics and parameters of total DX-8951f, including its moderately large Vss (mean, 14.36 L/m2 ; CV, 30.08%), moderately long elimination t1/2 (mean, 8.75 hours; CV, 48.34%), and substantial interindividual variability in clearance resemble those reported for topotecan.25-30 Interindividual variability in topotecan’s pharmacokinetic behavior is also large, and pertinent pharmacokinetic parameters are comparable to those reported for DX-8951f, with Vss and elimination t1/2 values averaging 19.3 ± 10.8 L/m2 and 3.6 ± 0.7 hours, respectively.24-29 However, this resemblance is most likely coincidental, because the principal mechanisms of drug disposition and clearance for DX-8951f and topotecan are different. The principal route of disposition for topotecan is renal clearance of the carboxylate species of the parent compound (36.3% ± 5.5%), whereas metabolism plays a less important role, accounting for the disposition of less than 1% of the total administered dose of the agent.1,3,43-45 However, hepatic metabolism of topotecan to a desmethyl metabolite may be more prominent in patients who are concurrently receiving treatment with anticonvulsant medications that induce P450 microsomal enzymes.45 In contrast, DX-8951f seems to be extensively metabolized by hepatic P450 systems in rodents, particularly P450 CYP3A and CYP1A.16 A pharmacologic study is planned to evaluate the impact of intrinsic P450 isoform variability, as assessed by 14C-erythromycin and caffeine metabolism, on the pharmacokinetic and toxicologic profiles of DX-8951f. The study will also evaluate the equilibrium between the lactone and ring-opened carboxylate forms of DX-8951 (Fig 1) and interindividual differences in protein bindings. The lack of a feasible analytic assay for the DX-8951 lactone at the initiation of the study precluded an evaluation of the kinetics of lactone ring opening. However, the cumulative results of pharmacologic studies of the camptothecin analogs, in which parallel measurements of both total drug and lactone were performed, indicate that the pharmacokinetic and pharmacodynamics of the lactone and total drug are similar, because the ratio of the lactone to total drug remains roughly constant.1,3,25-30,46 The preliminary results of an ongoing pharmacokinetics study indicate that the AUC of the DX-8951 lactone is approximately 30% to 35% of the total AUC. In essence, such results may be attributed to the fact that the open-ring carboxylate, albeit inherently inactive, serves as a pH-dependent reservoir for the active closed-ring lactone. In the present study, the relationships between the magnitude of DX-8951f-induced neutropenia and both AUC and Cmax values for total DX-8951 were well characterized by sigmoidal Emax models, which are more accurate than simple linear models at describing saturable physiologic effects, such as the percentage decrement in the ANC, in which Emax is 100%. Hypothetically, the ability to relate the magnitude of a principal toxicologic drug effect with drug exposure and/or dose suggests that the agent will be somewhat predictable in terms of toxicity, and supports attempts to develop individualized dosing schemes to optimize its therapeutic index. Furthermore, the satisfactory modeling of the principal toxic effect of DX-8951f using total drug supports the physiologic relevance and validity of measuring total drug instead of the active lactone, which is a cumbersome process.25,46 However, the results of ongoing studies, in which both total DX-8951 and lactone are being measured simultaneously, will shed further light on this issue. The antitumor activity observed in patients with various drug-refractory malignancies, including hepatocellular, colorectal, thymic, and extrapulmonary small-cell carcinomas, is encouraging and provides further impetus for the development of DX-8951f beginning with broad phase II evaluations. The antitumor activity noted in patients with colorectal carcinoma that progressed during treatment with irinotecan is especially promising. This observation should not imply that DX-8951f may have relevant activity against colorectal and other malignancies that are resistant to irinotecan, but it does suggest that DX-8951f may impact uniquely in some difficult clinical situations. It is also interesting to speculate that, in contrast with topotecan, which is a weak substrate for P-glycoprotein, DX-8951f may be active against neoplasms that constitutively overexpress P-glycoprotein, such as those derived from gastrointestinal tissues, as well as malignancies with acquired multidrug resistance. Although the ultimate clinical activity of DX-8951f will be defined only in appropriate phase II/III trials, DX-8951f’s specific pattern of myelotoxicity, its relative paucity of nonhematologic toxicity, and its activity against several types of neoplasms in early clinical evaluations warrant broad disease-directed evaluations of DX-8951f on this administration schedule, and possibly others.
Presented in part at the Eighteenth Annual Meeting of the American Society of Clinical Oncology, Atlanta, Georgia, May 15-18, 1999.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
/AUC
, MP.
) fit to the population model using an IT2S approach. The patient was treated with DX-8951f at the 0.5 mg/m2/d dose level.
