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Phase I and Pharmacokinetic Study of the Camptothecin Analog DX-8951f Administered as a 30-Minute Infusion Every 3 Weeks in Patients With Advanced Cancer

From the Department of Medicine, Gustave Roussy Institute, Villejuif, France, and Clinical Research Department, Daiichi Pharmaceuticals UK Ltd, London, United Kingdom.

Address reprint requests to Eric Raymond, MD, Department of Medicine, Institut Gustave Roussy, 39 Rue Camille Desmoulins, 94805 Villejuif, France; email raymond{at}igr.fr

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: DX-8951f is a totally synthetic derivative of camptothecin with greater cytotoxicity and more potent topoisomerase I inhibition than SN-38, topotecan, and camptothecin in preclinical studies. This phase I study aimed to describe the toxicity and to determine the maximum-tolerated dose (MTD) and pharmacokinetics of DX-8951f given as a 30-minute intravenous infusion every 3 weeks.

PATIENTS AND METHODS: Twelve patients with refractory solid malignancies were treated with DX-8951f at dose levels ranging from 4 to 7.1 mg/m². All but one patient had received previous chemotherapy, and eight patients were considered heavily pretreated. Total DX-8951f plasma concentrations were assayed using high-performance liquid chromatography.

RESULTS: Thirty-six cycles of DX-8951f were administered. Neutropenia was the dose-limiting toxicity, and it was dose-related, reversible, and noncumulative. Other toxicities included nausea and vomiting, alopecia, asthenia, fever, and anemia. Grade 1 or 2 diarrhea was observed in seven patients but was transient and resolved without requiring treatment. Pharmacokinetic analysis showed that DX-8951f had a half-life of 7.15 hours and a clearance rate of 1.65 L/h·m². The DX-8951f area under the plasma-concentration curve increased linearly with the dose. We defined the MTD of DX-8951f administered as a 30-minute intravenous infusion every 3 weeks as 7.1 mg/m².

CONCLUSION: The dose-limiting toxicity of DX-8951f is neutropenia. The recommended dose for phase II studies is 5.33 mg/m² every 3 weeks in patients previously treated with chemotherapy.

	INTRODUCTION

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CAMPTOTHECIN IS A cytotoxic alkaloid isolated from the Chinese tree Camptotheca acuminata.¹ The cytotoxic effect of camptothecin is mediated through the selective inhibition of the DNA topoisomerase I enzyme.² Despite significant antitumor activity in various experimental tumor models,^3-5 the severe and unpredictable toxicities of camptothecin precluded further clinical trials in the late 1960s.^6,7 A search for new camptothecin derivatives was therefore undertaken to overcome the high toxicity and the low solubility in water of the parent drug. This resulted in the discovery and development of several water-soluble camptothecin analogs, including irinotecan (CPT-11)^8,9 and topotecan.¹⁰

Mitsui et al¹¹ synthesized several new water-soluble camptothecin derivatives in an effort to retain potent inhibition of the topoisomerase I enzyme with a broad spectrum of antitumor activity and to decrease interpatient pharmacokinetic variability. They reported that hexacyclic analogs of camptothecin displayed superior topoisomerase I inhibitory activity.¹² From this family of compounds, they selected DX-8951f, a new hexacyclic camptothecin synthetic analog, as a potential candidate for further development (Fig 1).

View larger version (12K): [in this window] [in a new window]   Fig 1. Chemical structure of camptothecin analogs.

The lack of esterase-dependent activation, the aqueous solubility, the potency at inhibiting topoisomerase I, the broad antitumor activity, and the favorable toxicity profile make DX-8951f a good candidate for further clinical evaluation. The objectives of the present study were to determine the maximum-tolerated dose (MTD), to describe the principal toxicities, to assess the pharmacokinetic profile, and to evaluate the preliminary pharmacokinetic-pharmacodynamic relationships of DX-8951f. This phase I and pharmacologic study was performed using DX-8951f given as a 30-minute intravenous infusion every 3 weeks in patients with advanced cancers.

	PATIENTS AND METHODS

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Inclusion Criteria
Patients entered onto this study met the following criteria: (1) histologically confirmed solid tumor, unresponsive to standard therapy; (2) age 18 years; (3) minimum life expectancy of 3 months; (4) Southwest Oncology Group (SWOG) performance status 2; (5) no chemotherapy or radiotherapy within 4 weeks before treatment with DX-8951f (6 weeks for previous treatment with nitrosoureas, mitomycin, carboplatin, or extensive radiotherapy); (6) normal liver function, defined as bilirubin level 17 µmol/L, transaminase concentrations 2.5 times the upper limit of normal (ULN) ( five times ULN in cases of liver metastases), and alkaline phosphatase concentration 1.5 times ULN (unless due to bone metastases); (7) adequate bone marrow function, defined as leukocyte count 3,000/µL, neutrophil count 1,500/µL, platelet count 100,000/µL, and hemoglobin level 8.5 g/dL; (8) prothrombin time and activated partial thromboplastin time within normal limits; (9) psychosocial state compatible with the participation in the study; (10) signed informed consent according to institutional and national guidelines; (11) no kidney or liver failure; (12) no history of myocardial infarction within 6 months; (13) no history of chronic enteropathy, including ulcerative colitis and Crohn’s disease; (14) no uncontrolled systemic infection; (15) use of a reliable contraception for women of child-bearing age; (16) no known history of severe or life-threatening drug allergy or hypersensitivity to camptothecin derivatives; (17) absence of diarrhea or excess of two to three stools daily over normal frequency in the previous month; and (18) no symptomatic brain metastases.

Pretreatment and Follow-Up Examinations
SWOG performance status was measured and complete histories, physical examinations, and laboratory tests (complete blood count, blood creatinine, serum electrolytes, calcium, uric acid and protein, alkaline phosphatase, transaminases, total bilirubin, and albuminuria) were performed at baseline and repeated weekly. An electrocardiogram and a chest x-ray were obtained before treatment. Toxicity was evaluated by clinical and biologic examination on a weekly basis and graded using the common toxicity criteria of the National Cancer Institute.¹⁶ The dose-limiting toxicity (DLT) was defined as any of the following adverse events: (1) grade 4 thrombocytopenia; (2) grade 4 neutropenia lasting more than 5 days or febrile neutropenia; (3) grade 3 or higher nonhematologic toxicity, excluding nausea, vomiting, and alopecia; (4) grade 4 vomiting despite maximal antiemetic supportive care; and (5) any grade 3 or higher serious adverse event that would require intensive care. Tumors were evaluated and measured at baseline using appropriate morphologic examinations. Tumors were reassessed every other course, and responses were assessed using SWOG standard criteria.¹⁷

Treatment Procedure
DX-8951f (the methane sulfonate salt) was provided by Daiichi Pharmaceutical Co Ltd (Tokyo, Japan) in ready-to-use glass vials containing 5 mg of DX-8951f as the anhydrous free base equivalent in lyophilized powder form. DX-8951f was diluted with 5 mL of isotonic saline (0.9% NaCl) and removed from a 100-mL infusion bag to obtain a final stock 1-mg/mL solution. The appropriate volume of this stock solution was returned to the 100-mL plastic infusion bag in isotonic saline to yield the required dose. DX-8951f was administered as a 30-minute intravenous infusion every 3 weeks in the peripheral vein for the first dose and in a central vein for subsequent treatments.

Dose Escalation Procedure
The starting dose was 4 mg/m² every 3 weeks; the dose was escalated according to a modified Fibonacci scheme. A minimum of three patients per group were included at each dose level. If the DLT was observed in one of the first three patients entered at any dose level, an additional three patients were enrolled at that dose level. The clinical end point for this study was reached when the DLT occurred in two or more patients treated at the same dose level. After treatment of a group of three patients, a 100% dose escalation was allowed if no grade 2 or higher toxicity was observed. Otherwise, a 33% dose escalation was planned. Patients were treated at each dose level and observed for toxicity for at least 3 weeks before additional patients could be entered at that dose level. Toxicity was graded using the National Cancer Institute common toxicity criteria.¹⁴ The MTD was defined as the highest dose level at which more than 50% of patients experienced DLT after the first administration of DX-8951f.

Pharmacokinetics
Plasma and urine collection for pharmacokinetics. The pharmacokinetics of DX-8951f were determined during the first course of chemotherapy in at least two patients at each dose level. Heparinized blood samples (2.5 mL) were collected before the start of infusion (time 0) and at 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, and 24 hours after infusion. Blood was immediately centrifuged at 3,000 rpm for 15 minutes, and plasma was transferred to 1.5-mL sample tubes and stored at –20°C until needed for analysis. Urine samples were collected over 24 hours at 6-hour intervals from the start of the infusion; the volume was measured, and a 2-mL aliquot was frozen at –20°C.

High-performance liquid chromatography determination. The total DX-8951f concentrations in plasma and in urine were analyzed at Phoenix International Life Sciences (Montreal, Canada) using validated high-performance liquid chromatography methods with fluorescence detection.¹⁸ Briefly, after the addition of DW-8579 (1-amino-2,3-dihydro-9-ethyl-5-fluoro-9hydroxy-1H,12H-benzo(de)pyrano(3',4':6,7)indolizino(1,2-b)quinoline-10,13(9H,15H)-dione hydrochloride) as the internal standard, plasma samples were extracted using a solid-phase extraction step. The extracts were then chromatographed on an analytical column (MetaChem, Torrance, CA) using a mobile phase (1 mL/min) composed of 18% acetonitrile and 82% potassium phosphate buffer (0.05 mol/L, pH 3). The fluorescence detector wavelengths were set at 364 nm (excitation) and 446 nm (emission). Identification of the drug and the internal standard was based on the retention times of the pure compounds. A set of eight calibration standards was analyzed with every series of DX-8951f assays. For each calibration standard, the peak area ratio of DX-8951f to the internal standard was determined. A linear regression describing the calibration curve was then calculated using the reciprocal of the drug concentrations. The concentration of DX-8951f in each sample was calculated from the peak area ratio of DX-8951f in reference to a calibration curve. The lower limit of DX-8951f quantification was 0.20 ng/mL for plasma and 2.52 ng/mL for urine.

Pharmacokinetic analysis. Both noncompartmental and compartmental pharmacokinetic parameters for plasma DX-8951 were calculated. Noncompartmental analysis included the following: the area under the plasma concentration-versus-time curve from time 0 to the last measurable concentration (AUC 0-t) calculated by the linear trapezoidal method; the area under the plasma concentration-versus-time curve from time 0 to infinity (AUCinf), calculated as the sum of the AUC 0-t plus the ratio of the last measurable plasma concentration to the elimination rate constant; the maximum measured plasma concentration over the time span specified (Cmax); the terminal half-life (t_1/2); the volume of distribution at steady-state; and the total body clearance rate (CL), calculated as the dose divided by the AUCinf. In the pharmacokinetic study, a range from 10.0 to 2,000.0 ng/mL, reflecting the concentrations of subject samples, was analyzed. In addition, a cross-validation analysis was performed between the range 0.20 to 16.00 ng/mL and the range 10.0 to 2,000.0 ng/mL. For concentrations ranging between 0.20 and 16.00 ng/mL, the coefficient of linearity was 0.9998. For concentrations ranging between 10.0 and 2,000.0 ng/mL, the coefficient of linearity was 0.999. The coefficient of variation was 6.8% for the lowest concentrations. Individual plasma concentration-versus-time data were modeled separately using nonlinear least squares regression analysis (WinNonlin, version 1.0; Scientific Consulting Inc, Apex, NC).

Statistical analysis. The pharmacodynamic parameters neutrophil count, lymphocyte count, and WBC count were used to assess the relationship between hematologic toxicity and the pharmacokinetic parameters, such as AUCinf, Cmax, and CL. Student’s t test for the correlation coefficient r obtained by linear regression analysis was used. Two-sided P < .05 was considered significant.

	RESULTS

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Patients
The characteristics of patients entered onto this phase I study are listed in Table 1. All but one patient had received prior chemotherapy, with a mean number of two regimens per patient. Eight patients had received both prior chemotherapy and radiotherapy. Eight patients were considered heavily pretreated (ie, had received three prior chemotherapy regimens, or one prior chemotherapy regimen with anthracyclines, ifosfamide, or cyclophosphamide and/or abdominopelvic irradiation). A total of 36 cycles were administered at dose level ranging from 4 to 7.1 mg/m² (Table 2). The median number of courses administered per patient was two (range, one to 10). The dose levels investigated in this study are provided in Table 2. Among the four patients considered slightly pretreated, three were treated at dose level 2 and one was treated at dose level 3.

Dose reductions after febrile or prolonged grade 4 neutropenia (lasting > 5 days) were required in two patients treated at dose levels 2 and 3 and occurred at the first and second cycles, respectively. No evidence of cumulative hematologic toxicity was observed during the course of this study for patients treated at dose level 2 up to 10 cycles. No significant difference in terms of hematologic toxicity was observed in three patients considered as heavily pretreated compared with the three slightly pretreated patients who entered dose level 2. Other hematologic toxicities included grade 3 or 4 anemia in two patients, grade 3 or 4 lymphopenia in three patients, and grade 1 or 2 thrombocytopenia in five patients (Table 3). One patient treated at dose level 2 experienced grade 3 or 4 anemia at cycle 1, and another patient treated at dose level 3 had grade 3 or 4 anemia at cycle 2; both patients required transfusion.

A total of seven patients experienced grade 1 or 2 diarrhea—three patients at dose level 1 and four patients at dose level 2; none of the patients treated at dose level 3 experienced grade 1 or 2 diarrhea. No grade 3 or 4 diarrhea was observed. This diarrhea was delayed (median onset, day 3; range, 1 to 8 days), transient (median duration 24 hours; range, 0 to 9 days), and resolved without treatment.

Other toxicities included episodes of grade 1 or 2 fever without any sign of infection, which occurred during the first 24 hours after DX-8951f injection in three patients treated at dose level 2. Grade 1 or 2 alopecia was observed in two patients at dose level 1, three patients at dose level 2, and one patient at dose level 3. Grade 1 or 2 fatigue was reported in four patients at dose level 2.

One patient suffering from non–small-cell lung cancer was hospitalized for grade 3 atrial fibrillation which resolved after antiarrhythmic therapy with amiodarone. This patient had a past medical history of hypertension and a large lung tumor located close to the mediastinum. A relationship between the event and the study drug was considered possible.

Pharmacokinetics
The pharmacokinetics of DX-8951f were evaluated in all but two patients (two patients at dose level 1, five patients at dose level 2, and three patients at dose level 3). Estimations of pharmacokinetic parameters were similar in both noncompartmental or compartmental analyses. The DX-8951f peak plasma concentration was achieved at the end of the 30-minute intravenous infusion. Data for the noncompartmental pharmacokinetic parameters Cmax, AUC 0-t, AUCinf, CL, and t1/2 normalized for body surface area are summarized in Table 4.

Mean 24-hour urinary excretion accounted for 5% ± 4.24% (range, 1.10% to 14.88%) of the administered dose of DX-8951f.

Given the linear regression of pharmacodynamic parameters versus pharmacokinetic parameters, there was an apparent trend for the decrease in the neutrophil count to be proportional to the increase of the AUCinf (r² = .36, P = not significant).

Response
Eleven of the 12 patients were assessable for tumor response. Six patients had stable disease (lasting for 8 months in one patient), and five had progressive disease. No tumor response was observed.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
In the search for new camptothecin derivatives with a superior profile, DX-8951f may represent an advantage over other topoisomerase I inhibitors because of its higher in vitro potency at inhibiting topoisomerase I. It demonstrates broader and greater antitumor activity than CPT-11, SN-38, and topotecan, it has a favorable toxicity profile, and it lacks esterase-dependent activation and metabolism in preclinical studies.^11-15

We report here the results obtained in a phase I study of DX-8951f administered as a 30-minute intravenous infusion every 3 weeks. Neutropenia was the DLT of DX-8951f in this phase I study. The MTD for DX-8951f with this schedule was 7.1 mg/m,² since at this dose level two out of three patients experienced DLT, consisting of febrile or prolonged grade 3 or 4 neutropenia. Neutropenia seemed to be dose-related, reversible, and noncumulative. Neutropenia was also reported to be the DLT in a phase I study of DX-8951f administered as a 30-minute infusion daily for 5 days every 3 weeks.¹⁹

Interestingly, none of the patients treated in our phase I study experienced grade 3 or 4 diarrhea. Mild diarrhea was frequently observed, but it was not dose-related and it resolved rapidly without treatment. None of the other phase I trials, including those of the weekly,²⁰ the 24-hour infusion,²¹ and the daily-for-5-days schedules,¹⁹ reported any case of grade 3 or 4 diarrhea. The absence of severe diarrhea may represent an advantage of DX-8951f over CPT-11, especially in cases of previous abdominal or pelvic irradiation.

One patient treated with DX-8951f at 7.1 mg/m² died after the first cycle after developing acute respiratory distress syndrome with interstitial pneumonitis. The cause of the patient’s death was not fully elucidated because an autopsy was not performed. The acute respiratory distress syndrome could have been either a result of an infectious interstitial pneumonia or a toxicity of DX-8951f. Pulmonary toxicity has been described with other topoisomerase I inhibitors since pneumonitis occurred in patients treated with CPT-11 in two phase I studies.^22,23 In those studies, one patient with colon carcinoma and pulmonary metastases and two patients with small-cell lung cancer treated with a weekly schedule of CPT-11 developed dyspnea and a diffuse reticulonodular pattern on chest x-ray; two of these patients died of irreversible respiratory insufficiency. Therefore, we considered a possible relationship between the acute respiratory distress syndrome observed in our patient and the DX-8951f administration.

Although no formal statistical analyses were performed to determine the dose proportionality of Cmax and AUC, the AUC of DX-8951f seemed to increase linearly with the dose. This linear pharmacokinetic behavior was also reported in other phase I studies of DX-8951f administered daily for 5 day every 3 weeks or by 24-hour continuous infusion.^16,17 DX-8951f displayed a relatively long t_1/2 of 7 hours, comparable to that of CPT-11.^8,23 This could benefit an S-phase–specific agent by prolonging the exposure of tumor cells to DX-8951f in vivo. Cmax values exceed the concentrations required to inhibit tumor cell growth (0.01 mg/mL for 1 hour) in the human tumor cloning assay.¹⁹ Therefore, biologically relevant plasma concentrations were achieved and maintained for a relatively long duration using a single injection every 3 weeks. This possibly alleviates the need for intermittent or continuous administration schedules. Despite the limited pharmacokinetic data available in this study, pharmacodynamic evaluations suggested a decrease in circulating neutrophils with an increase in DX-8951f AUC and Cmax. In this study, we saw no evidence of cumulative toxicity to suggest an accumulation of drug that would have required us to repeat the sampling after cycle 1. In addition, in another phase I trial of weekly injections of DX-8951f, repeat pharmacokinetic evaluations were performed. To limit patient sampling in this study, we decided not to do repeated pharmacokinetic dosing.

In conclusion, the MTD of DX-8951f administered as a single 30-minute intravenous infusion every 3 weeks was 7.1 mg/m², since two out of three patients experienced DLT at this dose level. The MTD was reached rapidly at the third dose level of DX-8951f in this regimen. The recommended dose for phase II studies, based on the protocol design of our study, is 5.33 mg/m².

	ACKNOWLEDGMENTS

 
We gratefully acknowledge P. Dielenseger, M. Granier, and D. Leleu for their contribution to the pharmacokinetic sampling of this study. We also acknowledge Professor O’Grady, European Medical Director of Daiichi UK, and Professor Brendan Whittle, Consultant to Daiichi UK, for their input into the study set and for review of the manuscript.

	NOTES

 
V.B. and E.R. contributed equally to this work, and both should be considered as first authors.

Presented in part at the 1999 Annual Meeting of the American Association for Cancer Research, Philadelphia, PA.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted February 8, 2000; accepted July 6, 2000.

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