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Phase I and Pharmacokinetic Study of Exatecan Mesylate (DX-8951f): A Novel Camptothecin Analog

From the University of Texas M.D. Anderson Cancer Center, Houston, TX; Daiichi Pharmaceutical Corporation, Montvale, NJ; Phoenix International Life Sciences, Montreal, Canada; and United States Food and Drug Administration, Rockville, MD.

Address reprint requests to Paulo M. Hoff, MD, Box 78, Section of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; email: phoff{at}mdanderson.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetic (PK) profile, and recommended phase II dose of Exatecan mesylate (DX-8951f) when administered as a 24-hour continuous infusion every 3 weeks to patients with solid tumors.

PATIENTS AND METHODS: Twenty-two patients with advanced solid tumors, all previously treated, and with performance status 2, were entered. The starting dose of DX-8951f was 0.15 mg/m²; the dose was escalated according to the modified continual reassessment method. The drug was administered until disease progression or until unacceptable toxic effects occurred.

RESULTS: Seven dose escalations were completed, and a total of 53 courses were delivered (median, two courses; range, one to eight courses) during the study. At doses 1.2 mg/m² and lower, toxicities were mostly grade 1, primarily hematologic. In the initial cohort of three patients treated at 2.4 mg/m², grade 2 hematologic toxicity was observed. Of the six additional patients entered at 2.4 mg/m², three had grade 3 or 4 granulocytopenia. At doses higher than 2.4 mg/m², DLT granulocytopenia was observed. Nonhematologic toxicities, including nausea, vomiting, diarrhea, fatigue, and alopecia, were mild to moderate. Neither complete nor partial responses were observed, but four patients had stable disease. The PK profile of DX-8951f seemed linear at the doses administered. The plasma clearance, total volume of distribution, and terminal elimination half-life were approximately 3 L/h, 40 L, and 14 hours, respectively.

CONCLUSION: The DLT of this DX-8951f schedule was granulocytopenia for minimally pretreated patients, and both granulocytopenia and thrombocytopenia for heavily pretreated patients. The MTD for both minimally and heavily pretreated patients was 2.4 mg/m². DX-8951f seems to have a linear PK profile on the basis of single-dose administration. The recommended phase II dose with this schedule is 2.4 mg/m² for minimally pretreated patients. A lower dose should be used for heavily pretreated patients.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
THE CYTOTOXIC potency of camptothecin and camptothecin analogs is related to their ability to inhibit the catalytic activity of topoisomerase I (topo I), a nuclear enzyme involved in gene transcription and DNA replication.^1-3 Two semisynthetic camptothecin analogs, topotecan and irinotecan, are currently approved by the United States Food and Drug Administration for use in cancer therapy.

Exatecan mesylate (DX-8951f; Daiichi Pharmaceutical Co, Ltd, Tokyo, Japan) is a totally synthetic camptothecin analog with increased aqueous solubility, greater antitumor activity, and reduced toxicity compared with other available camptothecin analogs.⁴ In vitro studies have demonstrated that DX-8951f is three times more potent than SN-38, 10 times more potent than topotecan, and 20 times more potent than camptothecin.^4,5 Specifically, DX-8951f was shown to be more potent than SN-38 and topotecan against human tumor cell lines and clinical specimens in vitro and in vivo, including breast, lung, gastric, and colon cancers.^4-8 This agent was also shown to have broad antitumor activity against a large panel of human tumor xenografts in nude mice, including irinotecan- and vincristine-resistant tumors.^4-9

On the basis of encouraging preclinical data that suggest that DX-8951f could be an effective anticancer agent, we initiated this phase I study of this drug in patients with advanced solid tumors. DX-8951f is more active in multiple-dose regimens than with single dosing when the total dose is the same. Therefore, the schedule examined was a 24-hour continuous infusion every 3 weeks. The primary objectives were to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetic (PK) profile, and recommended phase II dose. A secondary objective was to document antitumor activity of this agent administered in this schedule.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Selection
Patients were eligible to participate if they had histologically confirmed, measurable, or clinically assessable solid tumor. Patients must have failed standard therapies. Patients had to be at least 18 years old, with a life expectancy of at least 12 weeks and World Health Organization performance status 2. Other eligibility criteria included adequate bone marrow; renal and hepatic functions as evidenced by absolute granulocyte count (ANC) 1.5 x 10³/mm³; platelet count 100 x 10³/mm³; hemoglobin 8.5 g/dL; creatinine 2.0 mg/dL; serum bilirubin 1.5 mg/dL; serum glutamic-pyruvic transaminase 2.5 times the upper limit of normal or 5.0 times the upper limit of normal for patients with liver metastases; and normal prothrombin time and activated partial thromboplastin time. Patients were excluded if they had received myelosuppressive chemotherapy within the previous 4 weeks (6 weeks for prior treatment with nitrosoureas or mitomycin C) or prior wide-field radiotherapy within the previous 4 weeks (2 weeks for radiotherapy to limited portals). Patients had to recover fully from prior chemotherapy- or radiotherapy-induced toxic effects. Women who were pregnant or lactating and women of childbearing age who were not using reliable means of contraception were excluded. Patients with carcinomatous meningitis, primary brain tumors, or active metastatic brain disease; concurrent severe or uncontrolled medical disease; chronic enteropathies; history of severe or life-threatening hypersensitivity reaction; or history of a positive serology for human immunodeficiency virus were also excluded. Informed consent was obtained in writing from all patients according to regulatory and institutional guidelines.

Treatment Plan
The starting dose of DX-8951f, calculated as the anhydrous free-base dose equivalent, was 0.15 mg/m² (one third the toxic dose low in the Beagle dog) administered as a single, 24-hour continuous infusion every 3 weeks. The dose-escalation scheme was based on the toxicities observed during the first course. For each dose escalation cohort, the dose was increased stepwise by doubling the dose until grade 2 or higher hematologic or nonhematologic toxicity was observed in at least one patient. Thereafter, doses were escalated according to the modified continual reassessment method.^10,11 Use of the modified continual reassessment method allowed for rapid dose escalation to levels that approach the ultimate phase II dose in that it selected the next higher dose level on the basis of Bayesian statistical estimation by using a mathematical model of the dose-toxicity relationship. The MTD was evaluated separately in minimally pretreated and heavily pretreated patients. Heavily pretreated patients were those who had received more than six courses of alkylating-agent–containing chemotherapy (or more than four courses of carboplatin or oxaliplatin), radiotherapy to more than 25% of hematopoietic reserves, and two or more courses of mitomycin C or a nitrosourea.

A minimum of 7 days was allowed between entry of patients at the same dose level. A minimum of 21 days, calculated from day 1 of the first treatment course of the last patient entered at the lower dose level, was allowed between dose escalation cohorts. In the event a DLT was observed, the DX-8951f dose was decreased by one dose level in subsequent courses administered to the same patient. If DLT also occurred at the lower dose level, the patient was removed from the trial. Intrapatient dose escalation was not allowed. No concurrent antitumor treatment was allowed except for localized palliative radiotherapy if other methods of pain control were ineffective. Prophylactic treatment for drug-related symptoms was not permitted during the first course. Thereafter, prophylactic treatment was allowed for grade 2 or higher nonhematologic toxicity.

DX-8951f was provided by Daiichi Pharmaceutical Corporation. Vials containing 2 or 5 mg of anhydrous free-base equivalent were reconstituted with normal saline to obtain a stock of 0.5 mg/mL of solution. The total daily dose to be administered by continuous infusion over 24 hours was divided into four equal 6-hour doses. Each 6-hour dose was prepared from a new stock solution immediately before administration. Care was taken to ensure that DX-8951f did not mix with any dextrose solution in the infusion line, because this agent is incompatible with dextrose solutions.

Pretreatment and Follow-Up Studies
Patients were evaluated by a physician before each course, and weekly contact was maintained and documented between the patient and research nurse. History and physical examination were performed before treatment and before each treatment course. A 12-lead ECG, chest x-ray, and other radiologic studies as indicated for tumor assessment were also performed before treatment. Radiologic studies required for tumor assessment were obtained every 6 weeks or as needed to confirm response. Complete blood counts with blood-cell differential were obtained before treatment, every 3 to 4 days during the first treatment course, and every 7 days during subsequent treatment courses. In addition, when the patient’s ANC dropped to less than 0.75 x 10³/mm³, hematologic monitoring was performed every other day until the ANC recovered to greater than 1.0 x 10³/mm³. Serum chemistry, electrolyte level, and coagulation profile were obtained before treatment, weekly during the first treatment course, and before each subsequent course. Abnormal values were monitored until they normalized. Urinalyses were performed before treatment and before each course.

All toxic effects were graded according to National Cancer Institute common toxicity criteria.¹² DLT was defined as febrile neutropenia ( 38.5°C) or more than 5 days’ grade 4 granulocytopenia, other grade 4 hematologic toxicity, grade 4 vomiting with maximum supportive care, any grade 3 nonhematologic toxicity (excluding nausea and vomiting), any grade 3 or higher adverse event requiring intensive care treatment, or the inability to start a second course after a 2-week delay caused by toxicity. The MTD was defined as the dose at which 20% of the patients experienced DLT during the first course.

Tumor measurement and serum tumor markers were performed before treatment and before each course. The tumor was reassessed by the same methods used to establish baseline measurements. For all responding patients (complete and partial responders), response was confirmed 4 to 6 weeks after it was first documented.

Sampling Schedule and Analytic Assay
Serial blood and urine samples were collected during and after the first dose of DX-8951f. Whole-blood samples (3.0 mL per time point) were drawn from the arm contralateral to the infusion line via venipuncture or indwelling intravenous cannula into a heparin-containing Vacutainer tube. Samples were collected at 0, 0.5, 1, 2, 6, 12, and 24 hours during infusion and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours after infusion. The collected blood was centrifuged at 3,000 rpm for 15 minutes to separate out the plasma. The plasma was then transferred to a sample tube and frozen immediately at -20°C. Urine samples were collected over 48 hours in two 24-hour collecting periods starting at the onset of DX-8951f infusion. At the end of each collection period, the total volume of urine was measured, and 50 mL of urine was drawn after adequate mixing of each bottle and frozen at -20°C.

All the collected plasma and urine specimens were labeled and forwarded to Phoenix International Life Sciences, Inc, Montreal, Canada, for PK analysis. DX-8951f in plasma and urine was analyzed with validated, high-performance liquid chromatography methods (Oguma et al, manuscript submitted for publication).¹³ The lower limit of quantitation was 0.20 ng/mL in plasma and 2.52 ng/mL in urine.

Pharmacokinetic Analysis
Pharmacokinetic analyses were performed with noncompartmental and compartmental methodologies. The latter were carried on by using a population methodology to ensure the robustness of the results. Two- and three-compartment PK models were investigated for their ability to simultaneously describe plasma concentrations and excreted urinary amounts of DX-8951f after its administration via 24-hour intravenous infusion. No difference in the quality of fit was seen between these two models. The two-compartment model was therefore chosen as being the simplest at describing adequately the plasma concentrations and excreted urinary amounts of the drug. During the model discrimination process, clearances and volumes were better fitted (ie, lower Akaike information criterion test values) when they were expressed in terms of ideal body weight (IBW) than as body-surface area or actual body weight. The schematic representation of this PK model is presented in Fig 1. Parameters defined and fitted by the model were central volume of distribution, peripheral volume of distribution, distributional clearance, renal clearance, and nonrenal clearance. During the population PK analysis, clearances and volumes of distribution were fitted to the average observed patient’s IBW, calculated for each patient with the equations from Devine:¹⁴

View larger version (12K): [in this window] [in a new window]   Fig 1. Structural pharmacokinetic model for DX-8951f. Abbreviations: Vc, volume of distribution; Vp, peripheral volume of distribution; CLd, distributional clearance; CLR, renal clearance; CLNR, nonrenal clearance; IV, intravascular.

Men: IBW (kg) = 50 + 2.3 x (height in inches > 5 feet)

On average, 15 plasma and urine observations were fitted simultaneously per patient by the population PK model. Individual PK parameter estimates were first derived with ADAPT-II (Biomedical Simulations Resource, Los Angeles, CA) by using maximum likelihood analysis.¹⁵ These estimates were then used as prior values for the population PK analysis, which was performed with IT2S (SUNY, Buffalo, NY).¹⁶

All plasma concentrations and excreted urinary amounts of DX-8951f were modeled simultaneously by using a weighting procedure of W_j (weight associated with each individual concentration time point j) = 1/S_j². The variances S_j² (variance calculated for each individual concentration time point j) were calculated for each observation y_J (observation for each individual concentration time point j) by using the equation S_j² = (a + b·Y_j),² where a and b are the intercept and slope of each variance model. The slope is the residual variability associated with each concentration or urinary excreted amount (includes the intraindividual variability and all experimental errors), and the intercept is related to the limit of detection of the analytic assay. Variance parameter estimates were derived with maximum likelihood analysis. These estimates were used as beginning priors and were updated iteratively during the population PK analysis until stable values were found. Three different variance models were fitted, one for the plasma concentrations observed during the infusion period, a second for the plasma concentrations observed during the period after the end of the infusion, and a third variance model for the urinary amounts of DX-8951f excreted.

Pharmacodynamic Analysis
The relationship between the maximum observed decrease in WBC, ANC, and platelets at nadir compared with their baseline value versus the exposure of the patient to DX-8951f were determined by using a conventional estimated maximum decrease (E_max) model.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Characteristics
Twenty-two patients were enrolled onto the study. All had histologically confirmed diagnosis of solid tumor: one patient had bronchioalveolar carcinoma, and the remainder had either colon or rectal adenocarcinoma. The median World Health Organization performance status was 0 (68%). All 22 patients had received prior chemotherapy, 19 had prior surgery, and five had prior radiotherapy. Of the patients who had prior chemotherapy, three had received one chemotherapeutic agent, four had received two, 11 had received three, and four had received more than three. Sixteen (73%) patients were previously treated with other topo I inhibitors. The patients’ characteristics are listed in Table 1.

Nonhematologic toxic effects included nausea, vomiting, asthenia, and moderate alopecia in approximately 82%, 55%, 46%, and 46% of patients, respectively. Diarrhea was common (41%) but was often mild. Stomatitis was mild and infrequent. One patient developed a transient grade 2 increase in serum lipase with signs of pancreatitis of short duration. No drug-related hepatic, renal, or neurologic toxicities were observed. No toxic deaths occurred. The toxicity profile of DX-8951f seemed to be dose related and predictable. The toxicities observed are listed in Tables 4 and 5.

Pharmacokinetic Analysis
The PK profile of DX-8951f was determined in all patients during the first drug infusion. Plasma PK parameters are listed in Table 6. No differences were seen between noncompartmental and compartmental methods. The latter was, however, necessary to perform to characterize fully the PK profile of the drug. The plasma concentrations and excreted urinary amounts of DX-8951f were simultaneously fitted in each subject with a two-compartment PK model. The goodness of fit was very good and is presented for a representative subject in Fig 2. The PK behavior of DX-8951f was linear between doses, in that plasma clearance (CL) and total volume of distribution (Vss) did not change between the lowest and highest dose groups. When mean area under the plasma concentration–time curve from time zero to infinity (AUC_inf) was plotted against dose, AUC_inf increased linearly with the dose. Similarly, mean maximal measured plasma concentration (C_max) increased linearly with dose ( Table 7). When adjusted for body surface area (BSA), the regression slope for CL and Vss did not change with dose adjusted for BSA. Furthermore, when CL unadjusted for BSA was plotted against dose adjusted and unadjusted for BSA, CL did not change with the administered dose. Indeed, a one-way analysis of variance indicated that CL did not vary with the administered doses (P = .96). These results indicate that the PK of DX-8951f is linear. On the basis of the sampling schedule of up to 24 hours after the end of infusion, the approximate PK parameters of DX-8951f were terminal elimination half-life (T_1/2) of 14 hours, CL of 2.9 L/h, and Vss of 40 L. The mean percentage of DX-8951f excreted unchanged in the urine was 8.9%.

View larger version (15K): [in this window] [in a new window]   Fig 2. Plasma concentrations and excreted urinary amounts of DX-8951f administered by a 24-hour infusion in a representative patient.

View larger version (12K): [in this window] [in a new window]   Fig 3. Effect of DX-8951f exposure on absolute granulocyte count (ANC) with an estimated maximum decrease (Emax) model.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

Currently, two camptothecin analogs are available commercially: topotecan and irinotecan. Topotecan is indicated for patients with metastatic ovarian carcinoma after failure of initial or subsequent therapy^21-23 and with small-cell lung cancer after failure of first-line chemotherapy.^24,25 Irinotecan is approved for the treatment of metastatic colorectal carcinoma that is refractory to fluorouracil.^26-28 Compared with available camptothecin analogs, DX-8951f is a more potent inhibitor of topo I, and preclinical studies have demonstrated broad antitumor activity,^4-9 making DX-8951f an attractive compound for clinical development.

In our trial, hematologic toxicity, primarily granulocytopenia, was the principal DLT of DX-8951f. In this respect, the toxicity of DX-8951f and topotecan were similar.^29-31 This is in contrast to irinotecan; its primary toxicity was diarrhea.^26,32 At the dose levels that produced hematologic DLT, no grade 3 or 4 nonhematologic toxicities were noted. When administered by 24-hour continuous infusion every 3 weeks, the MTD of DX-8951f was 2.4 mg/m² for both minimally pretreated and heavily pretreated patients. For minimally pretreated patients, the recommended phase II dose is 2.4 mg/m². However, for heavily pretreated patients, it is reasonable to use a lower dose in the range of 1.2 to 2.4 mg/m², because these doses were well tolerated.

After single-dose administration to solid-tumor patients, the PK profile of DX-8951f seems linear between dose groups (0.15 to 3.6 mg/m²). The C_max correlated with drug clearance such that patients with lower drug clearances had higher C_max values. Because the terminal elimination half-life of DX-8951f is 14 hours, administering the drug by an infusion duration of two half-lives means that the C_max will approximate (75%) the value of the concentration at steady state (C_ss). Because C_ss is dependent on the CL and the administered dose (C_ss = dosing rate/CL), the C_max obtained after a 24-hour infusion of DX-8951f predicts the CL. This relationship would obviously not be present if the drug were administered over a short duration, such as a 30-minute infusion. In the PK compartmental analysis, linear two- and three-compartment PK models were investigated for their quality of fit. These two models described equally well the PK profile of DX-8951f. This similarity in the quality of fit between the two models could be explained by the fact that the long infusion probably masked the distribution phase between the central and peripheral compartment. During the model discrimination process, it was found that the best fit was obtained when clearances and volumes of distributions were expressed in terms of kilograms of IBW and not per meter squared of body-surface area or kilograms of actual body weight. This suggests that dosing of the drug may correlate better with targeted drug concentrations when given per kilogram of IBW. This observation will need to be confirmed by other future PK studies. Relationships were found between DX-8951f plasma exposure and the decrease in the ANC and platelet nadir compared with their baseline predose values.

The observed disease stabilization in a patient with colon cancer previously treated with irinotecan in this study is encouraging. However, the clinical activity of DX-8951f in patients with advanced colorectal carcinoma and other tumors will ultimately be ascertained through appropriate phase II trials.

	ACKNOWLEDGMENTS

 
Supported by a contract from Daiichi Pharmaceutical Corporation, Montvale, NJ.

	NOTES

 
This article was prepared by Dr Richard Pazdur in his private capacity. No official support or endorsement by the Food and Drug Administration is intended or should be inferred.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted August 17, 2000; accepted November 15, 2000.

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