Clinical Cancer Research Bridging the Lab and the Clinic in Cancer Medicine
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sharma, S.
Right arrow Articles by Saltz, L. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sharma, S.
Right arrow Articles by Saltz, L. B.
Clinical Cancer Research Vol. 7, 3963-3970, December 2001
© 2001 American Association for Cancer Research

Clinical Trials

Phase I Study of Topoisomerase I Inhibitor Exatecan Mesylate (DX-8951f) Given as Weekly 24-Hour Infusions Three of Every Four Weeks

Sunil Sharma1, Nancy Kemeny, Gary K. Schwartz, David Kelsen, Eileen O’Reilly, David Ilson, John Coyle, Robert L. De Jager, Martin P. Ducharme, Sarah Kleban, Ellen Hollywood and Leonard B. Saltz

Division of Gastrointestinal Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021 [S. S., N. K., G. K. S., D. K., E. O., D. I., S. K., E. H., L. B. S.]; MDS Pharma Services, Montreal, Canada H4R 2N6 [M. P. D.]; and Daiichi Pharmaceutical Corporation, Montvale, New Jersey 07645 [J. C., R. L. D. J.]


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Exatecan mesylate (DX-8951f) is a topoisomerase I inhibitor that has increased solubility and antitumor activity compared with other topoisomerase I inhibitors. The purpose of this study was to establish a safe dose of DX-8951f given as a weekly 24-h infusion 3 of every 4 weeks. DX-8951f was administered as a 24-h continuous infusion in escalating doses. Twenty-seven patients were treated with 81 courses of the drug. Dose-limiting toxicities included neutropenia, thrombocytopenia, and inability to administer all three doses in the first cycle. In minimally pretreated patients, a dose of 0.8 mg/m2 was tolerable. In patients who were heavily pretreated, a slightly lower dose, 0.53 mg/m2, was tolerated without any severe toxicities. Nonhematological toxicities were mild and consisted of mild diarrhea, asthenia, mild nausea, and constipation. Pharmacokinetic parameters could be well described with a one-compartment model in most patients, although the application of the one-compartment model probably resulted in an underestimated elimination half-life. In conclusion, the recommended Phase II dose for DX-8951f administered as a weekly 24-h infusion on a 3-of-4 week schedule is 0.8 mg/m2 in minimally pretreated patients and 0.53 mg/m2 in patients who are heavily pretreated.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
CPT2 is an alkaloid extracted from the plant Camptotheca acuminata. The cytotoxic potencies of CPT and CPT analogues are related to their ability to inhibit the catalytic activity of the nuclear enzyme Topo I, which is involved in gene transcription and DNA replication (1) . Topo I is an enzyme that relaxes supercoiled DNA during replication and transcription. Topo I binds covalently to double-stranded DNA and forms a break in one strand; this intermediate is known as the cleavable complex. The intact strand is passed through the gap in the broken strand, which is then resealed, and the enzyme dissociates from the helix. CPTs bind to the Topo I-DNA cleavable complex and prevent resealing of the DNA (1) .

DX-8951f (Fig. 1)Citation is a synthetic analogue of CPT and was synthesized to increase solubility and enhance antitumor efficacy. The anhydrous free base form of the drug is referred to as DX-8951. In vitro studies demonstrated more potent activity of DX-8951f than SN-38 and topotecan against various types of human tumor cell lines, including breast, lung, gastric, and colon cancer (2, 3, 4) . In the human tumor cloning assay, DX-8951f showed dose-dependent inhibition of clonogenic cells from head and neck, liver, non-small cell lung, breast, colon, ovary, and prostate tumors (5 , 6) . DX-8951f also has a broad spectrum of activity in human tumor xenografts of breast, lung, gastric, pancreatic, esophageal, and colon carcinomas implanted in nude mice (3 , 4 , 7, 8, 9) . These include CPT-11-resistant non-small cell lung and pancreatic tumors.



View larger version (8K):
[in this window]
[in a new window]
  		Fig. 1. Chemical structure of DX-8951f (molecular formula, C24H22FN3O4·CH4O3S · 2H2O. Mr 567.59).

 
Much like CPT-11 and topotecan, the active lactone form of DX-8951f exists in a pH-dependent equilibrium with the respective hydroxy species (10) . In pharmacology studies in dogs and mice, the t1/2 values for lactone and total DX-8951 were similar. The calculated AUC for lactone is ~50% of the total drug AUC, and AUC is linearly related to dose.

In metabolism studies carried out in vitro with human liver microsomes, major metabolites of DX-8951f were the 4-hydroxy-methyl form of DX-8951 (UM-1) and the 4-hydroxylated form (UM-2; Ref. 10 ). There was good correlation between the amounts of UM-1, UM-2, and UM-3 produced by the microsomes and the hydroxylating activity at the 6-ß position of testosterone, which is an index of CYP3A activity. Production of UM-2 was also inhibited by the CYP1A-specific inhibitor {alpha}-napthoflavone. In addition, production of the metabolites was strongly inhibited by CYP3A-specific inhibitors such as ketoconazole, erythromycin, and troleandomycin. These results indicate that DX-8951f is metabolized mainly by CYP3A enzymes (10) .

In toxicology studies in mice, rats, and dogs, bone marrow suppression, gastrointestinal toxicity, and mutagenicity were principally observed. Hematological toxicity was dose limiting in all species, and the toxic dose low values in the most sensitive species (dog) were 10 mg/m2 (0.5 mg/kg) for the single dose, 0.3 mg/m2/day (0.015 mg/kg/day) for five daily doses, and 0.5 mg/m2 (0.025 mg/kg) for the single 24-h continuous infusion schedule (10) . In other in vivo studies, a cyclical dosing pattern at lower doses of DX-8951f improved antitumor activity over single-dose administration. On the basis of these preclinical data, several schedules were chosen for intermittent administration. These included daily for 5 days every 3 weeks, 24-h infusions weekly, and once a week for 3 of every 4 weeks (9 , 11) .

The clinical development of DX-8951f was based on its significantly higher potency in vitro and its relatively favorable toxicity profile in preclinical studies. The present Phase I and pharmacological study had the following objectives: (a) characterize the toxicities of DX-8951f administered as three weekly 24-h infusions every 4 weeks; (b) determine the MTD and recommended Phase II dose; (c) assess the pharmacological behavior of DX-8951f on this schedule; and (d) seek preliminary evidence of antitumor activity.


   PATIENTS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Selection.
Patients with histologically confirmed solid tumors that had failed standard therapies were included in the study. All patients were >=18 years of age, signed a written informed consent, and had an Eastern Cooperative Oncology Group performance status of 0–2. Other inclusion criteria included measurable or clinically evaluable disease, adequate hematological (ANC >=1.5 x 103/mm3; platelet count >=100 x 103/mm3; hemoglobin >=8.5 g/dl), renal (serum creatinine <=2.0 mg/dl), and hepatic function (serum bilirubin <=1.5 mg/dl; aspartate aminotransferase <=2.5 x upper limit of normal or <=5.0 x upper limit of normal if patient had liver metastases). The study was approved by the Institutional Review Board of Memorial Sloan-Kettering Cancer Center.

Drug Administration.
The starting dose of DX-8951f, calculated as the human equivalent of one-third of the dog toxic dose low for a single 24-h infusion divided by 3, was 0.05 mg/m2/24 h. Dose levels explored were 0.05, 0.1, 0.15, 0.23, 0.35, 0.53, 0.8, 1, and 1.2 mg/m2/24 h. This escalation scheme is consistent with a modification of the Fibonacci sequence. One patient was entered at the lowest dose level. When no patients experienced toxicity at a dose level, only one patient was treated at the next dose level. When moderate or worse toxicity was experienced at a dose level, at least three patients were treated at that dose level. If one patient of a group of three experienced a DLT, the group size was increased to six patients. If two of a maximum of six patients developed DLT at the same dose, that dose was considered to be above the MTD. MTDs were evaluated separately in HP and MP patients, according to pretreatment status. HP patients were defined as those who had received more than six courses of alkylating agent-containing chemotherapy (or more than four courses of carboplatin), radiation therapy to >25% of hematopoietic reserves, or two or more courses of mitomycin C or a nitrosourea. In the MP group, a minimum of six patients were to be treated at the MTD. The MTD was defined as one dose level below the dose that induced DLTs in two of six patients. DLT was defined as grade 4 neutropenia that was prolonged (>5 days) or accompanied by fever, grade 4 thrombocytopenia, any grade 3 nonhematological toxicity (except vomiting, in which case the criterion was grade 4 with maximal support), inability to administer three weekly doses in cycle 1, or >1 week delay in starting cycle 2. All toxicity grading was performed according to the National Cancer Institute’s Common Toxicity Criteria.

DX-8951f was supplied by Daiichi Pharmaceuticals (Montvale, NJ) as 2 or 5 mg of anhydrous free base equivalent/vial and was diluted in the vial with 0.9% NaCl USP to obtain a stock 0.5 mg/ml solution. The appropriate volume of stock solution to yield the required dose was diluted in a polyvinyl chloride infusion bag with sterile 0.9% NaCl to a total volume of 96 ml. This was administered by i.v. infusion over a 24-h period through a central venous catheter with a programmed peristaltic pump system. All treatment was done on an outpatient basis. After reconstitution with normal saline, DX-8951f is stable for at least 24 h under ambient conditions of light and temperature.

Pretreatment Evaluation and Follow-Up Studies.
Baseline evaluation was carried out within 10 days prior to treatment initiation and included informed consent, a detailed medical history, comprehensive physical examination, 12-lead electrocardiogram, chest X-ray, complete blood count, differential count, serum chemistries, electrolytes, prothrombin time, pregnancy test, and urinalysis. Patients were seen by a physician before each treatment course. Tumor measurements/serum tumor markers were performed using appropriate tests at baseline and after each course of therapy.

A complete response was defined as the disappearance of all disease, documented by measurements separated by at least 4 weeks, and a partial response was defined as >=50% reduction in the sum of bidimensional products of all measurable lesions documented by at least two measurements separated by at least 4 weeks.

PK Sampling and Assay.
Blood samples were collected before the start of the first infusion (time 0) and at 0.25, 0.5, 0.75, 1, 2, 6, 24, 24.25, 24.50, 24.75, 25, 26, 28, and 30 h after the beginning of the first infusion. The complete urine output was collected from time 0 to 24 h and from 24 to 48 h after the beginning of the first infusion. Plasma and urine samples were also collected at the same time before and after the beginning of the third weekly infusion of DX-8951f in 17 patients. In the remaining 10 patients, plasma and urine samples were collected only after the first dose.

Blood was collected in a heparinized tube and was centrifuged at 3000 rpm for 15 min to separate the plasma. Plasma was stored at -20°C while awaiting dispatch. Urine samples were collected in sterile wide-mouthed plastic bottles. After each bottle containing the urine was shaken, a measured quantity of ~50 ml was drawn off and frozen at -20°C in a suitably labeled sample tube.

Total concentrations of DX-8951 (lactone plus hydroxy-acid forms) were determined by high-performance liquid chromatography. The plasma and urine concentrations were used to determine the PK parameters by standard noncompartmental and compartmental analysis (12) . Three different compartmental PK models were compared in terms of their ability to describe simultaneously the observed plasma concentrations and the excreted urinary amounts of DX-8951. Discrimination between these candidate compartmental PK models was performed by looking at pertinent graphics (e.g., fitted and observed concentrations versus time, weighted residuals versus observed values), by maximizing the coefficient of determination values (R2), and by minimizing the Akaike information criterion test and the residual variability. No difference in the quality of fitting was observed among all three models except for the Akaike information criterion test, which was lower for the one compartment. It was therefore the most appropriate one to use, and the parameters defined by this model were: volume of distribution (Vss; liters/m2) and clearance (CL; liters/h/m2). On average, 18 observations per patient were fitted simultaneously by the model. Individual PK parameter estimates were first derived with ADAPT-II (13) using maximum likelihood analysis. These estimates were then used as prior values for the population PK analysis, which was performed using an iterative two-stage methodology (IT2S; Ref. 12 ). All concentrations were modeled using a weighting procedure of Wj = 1/Sj2, where the variance 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, which includes the intraindividual variability and the sum of all experimental errors, and the intercept is related to the limit of detection of the analytical assay. Two variance models were used, one for the urinary observations and the other for the plasma concentrations of DX-8951. Variance parameter estimates were derived using maximum likelihood analysis (ADAPT II). These estimates were used as beginning priors and were updated iteratively during the population PK analysis (IT2S) until stable values were found. Data from five patients were not included in the population analysis because their concentration-time data on day 1 were not consistent with those on day 15 (i.e., the values were judged to be anomalous). Concentration-time data for these patients were therefore fitted by allowing a difference between the day 1 and day 15 administered doses. PK parameters were calculated in these patients with a Bayesian algorithm (MAP-B, ADAPT II) using the results of the IT2S population analysis from the other patients.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Twenty-seven patients were treated with 81 courses of DX-8951f. Patient characteristics are listed in Table 1Citation . Eleven of 27 patients had previously received both chemotherapy and radiation, and all patients had been previously treated with chemotherapy. The dose escalation scheme and number of patients treated at each dose level are listed in Table 2Citation . The dose was increased stepwise for each dose escalation cohort, first by doubling the starting dose to dose level 2, and then by increasing the dose by increments of 50% until hematological or nonhematological toxicity >=grade 2 (moderate) was observed in at least one patient with the exception of certain grade 2 laboratory tests already elevated to grade 1 at baseline (e.g., hemoglobin and bilirubin). Thereafter, the dose was increased by increments of 33%.


View this table:
[in this window]
[in a new window]
  		Table 1 Patient characteristics

 

View this table:
[in this window]
[in a new window]
  		Table 2 Dose levels

 
Hematological Toxicities.
The most serious toxicities for DX-8951f were hematological (Table 3)Citation . The median platelet and neutrophil nadir decreased with increasing doses (Table 3)Citation , and four patients demonstrated dose-limiting hematological toxicity at a dose level of 1.2 mg/m2 (Table 4)Citation . None of the patients who experienced dose-limiting neutropenia had to be hospitalized for sepsis. No platelet transfusions were required in patients experiencing dose-limiting thrombocytopenia. DLTs were seen at various dose levels for HP and MP patients. At doses of 1.2 mg/m2 and 1.0 mg/m2, four of five and two of four MP patients enrolled at each respective dose level experienced DLT. One of six MP patients experienced DLT at a lower dose of 0.8 mg/m2. Both of the HP patients receiving 0.8 mg/m2 experienced DLT. A slightly lower dose of 0.53 mg/m2 was tolerated without any severe toxicities or DLT in the three patients treated at that dose level. Interpatient variability was observed at the various dose levels, but toxicity increased in grade at higher doses. Six patients required dose reductions because of severe dose-limiting hematological toxicity (two patients at 0.8 mg/m2 dose level (one HP, one MP), two patients at 1.0 mg/m2 dose level (two MP), and two patients at 1.2 mg/m2 dose level (two MP). Minor hematological toxicities included grade 3 anemia (11%), grade 2 neutropenia (4%), and grade 3 neutropenia (7%).


View this table:
[in this window]
[in a new window]
  		Table 3 Hematological toxicity (cycle 1)

 

View this table:
[in this window]
[in a new window]
  		Table 4 DLTs

 
Nonhematological Toxicities.
DX-8951f was well tolerated with only mild nonhematological toxicity (Table 5)Citation . Unlike irinotecan, diarrhea was observed in only 9% of courses, and it was mild. No patients required hospitalization for diarrhea or dehydration. Other toxicities included constipation (25%) and nausea (25%) leading to grade 1 or 2 vomiting in a minority of courses (14%). Although asthenia was difficult to ascribe to DX-8951f, it was a frequent clinical toxicity (27%). It was almost always mild (grade 1 or 2), with only one patient experiencing grade 3 asthenia. Neurosensory symptoms were reported in 26% of courses and consisted mostly of grade 1 numbness of upper and lower extremities.


View this table:
[in this window]
[in a new window]
  		Table 5 Nonhematological toxicities

 
Antitumor Activity.
No objective responses were observed in this trial. Five patients exhibited stable disease. Three patients had a diagnosis of colorectal cancer and had stable disease for an average of six cycles. Interestingly, all of these patients had already received and had progressed on prior therapy with irinotecan. One patient with pancreatic cancer and another with hepatocellular carcinoma had stable disease for 9 and 22 cycles of therapy, respectively.

PK Studies.
Total plasma pharmacokinetics were obtained in all 27 patients and were analyzed using both noncompartmental and compartmental analyses. Compartmental PK results were more robust than noncompartmental analyses because 30 h of sampling in the plasma and 48 h of urinary data were simultaneously modeled. The results of compartmental analyses are presented in Table 6Citation . The mean plasma elimination half-life was 7.13 h. Total-body clearance did not vary with dose (mean, 1.73 liters/h/m2), indicating linear pharmacokinetics within the administered dose range (Fig. 2)Citation . The percentage of the administered dose eliminated unchanged in the urine (FE) was 10.66%. The Vss was modest and was independent of the dose with a mean value of 12.7 liters/m2 (Fig. 3)Citation . Fig. 4Citation demonstrates that 40% of the variability in plasma clearance of the drug is explained by variation in the cmax. This is expected because of the long duration of the infusion. PK parameters could be well described using a one-compartment model as demonstrated by the quality of fit in a representative patient (Fig. 5)Citation . Five patients were excluded from the population PK analysis and were analyzed separately because of anomalies between the day 1 and day 15 data in these patients. Specifically, the cmax on day 15 was either much higher or much lower than that of day 1. Various reasons were retrospectively examined, including time of sample collection, adequacy of sample labeling, nonlinear PK processes in these patients, concomitant medications, and liver or renal dysfunction. It was found that the observed differences in the cmax were not consistent among patients: sometimes it increased markedly on day 15 or decreased markedly. In the remaining 22 patients, the cmax between the two dosing days were consistent and indicative of linear PK processes. The most likely hypothesis for the observed differences in the five patients was that it was indicative of a "noisy" data set probably because of inaccuracies in the amounts and timing of the doses administered. The PK data for these patients were therefore analyzed separately, using a Bayesian control algorithm as described in the "Patients and Methods" section. This allowed us to calculate the PK parameters for these patients and report them without biasing markedly the results of the population analysis itself.


View this table:
[in this window]
[in a new window]
  		Table 6 PK analysis of DX-8951f

Data from five patients were not included in the population analysis because their concentration-time data on day 1 were not consistent with those on day 15 (i.e., the values were judged to be anomalous).

 


View larger version (14K):
[in this window]
[in a new window]
  		Fig. 2. Relationship between the estimated clearance values (CL) fitted by compartmental analysis and the different administered doses (µg/m2) of DX-8951f.

 


View larger version (14K):
[in this window]
[in a new window]
  		Fig. 3. Relationship between the estimated values of the volume of distribution (Vss) fitted by compartmental analysis and the different administered doses (µg/m2) of DX-8951f.

 


View larger version (13K):
[in this window]
[in a new window]
  		Fig. 4. Relationship between the estimated clearance values (CL) fitted by compartmental analysis and the different observed cmax values (µg/L) of DX-8951 after a 24-h i.v. infusion (day 1).

 


View larger version (13K):
[in this window]
[in a new window]
  		Fig. 5. Fitted (solid line) and observed (•) plasma concentrations (top) and excreted urinary amounts (bottom) of DX-8951 after a 24-h i.v. infusion in a representative patient.

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Topo I is an important nuclear enzyme that is required for relaxation of torsionally strained duplex DNA (14) . Several studies have indicated that tumor cells may have a higher amount of Topo I compared with surrounding normal tissues. These include studies with colon, ovarian, and esophageal cancers (15, 16, 17, 18) and in non-Hodgkin’s and other lymphomas (19) . Topo I is a target for CPT (20) , which appears to stabilize adducts containing the Topo I bound to the cleavable complex (21) . In recent years, several analogues of CPT, including irinotecan (CPT-11) and topotecan, have been approved for human use against a variety of tumors in the United States.

DX-8951f is a synthetic CPT with increased solubility and antitumor efficacy in vitro. In preclinical studies, the principal DLT of this drug was myelosuppression on all tested schedules. We performed a Phase I trial in humans with advanced cancer to determine the MTD of DX-8951f administered as a weekly 24-h infusion 3 of every 4 weeks.

DX-8951f was generally well tolerated. The DLT of neutropenia, thrombocytopenia, or inadequate doses (less than three) in cycle 1 was seen at 1.0 mg/m2 in MP patients and at 0.8 mg/m2 in HP patients. The MTD was defined as 0.8 mg/m2 for MP and 0.53 mg/m2 for HP patients. Neutropenia and thrombocytopenia were dose related, although no patients required hospitalizations for neutropenic fevers.

Nonhematological toxicity was mild with diarrhea observed in 9% of courses. No patients required hospitalization for diarrhea or dehydration. This is in contrast to treatment with irinotecan, where overall incidence of delayed diarrhea was 87% (in ~60% of the cycles administered; Ref. 22 ). Other nonhematological toxicities included constipation (19%) and nausea (25%) leading to grade 1 or 2 vomiting in a minority of courses (14%). Although asthenia was difficult to ascribe to DX-8951f, it was a frequent clinical toxicity (27%).

Neutropenia was the DLT of DX-8951f on all of the alternative schedules (daily for 5 days, weekly for 3 of every 4 weeks, every 3 weeks, and continuous infusion over 5–21 days) for MP patients, whereas neutropenia and thrombocytopenia were dose limiting in HP patients (23, 24, 25, 26, 27) . Neutropenia is also the principal toxicity described with other Topo I inhibitors (irinotecan and topotecan). The incidence of grade 3 or 4 neutropenia with irinotecan and topotecan is 12–20% and 30–80% of treatment cycles (22) . In other trials of DX-8951f, two cases of acute pancreatitis not predicted by preclinical toxicology were also observed (28) .

The PK parameters for most patients indicated high inter- and intrapatient variability, which is not unlike that observed with irinotecan (29, 30, 31) . The reasons for this variation are not well understood at this time and may be related to pharmacogenetic variations in DX-8951f metabolism. For most patients, the pharmacokinetics of the drug appeared linear as evidenced by a lack of relationship between the administered dose and either clearance or Vss (Figs. 2Citation and 3Citation ). The PK analysis was well described using a one-compartment model, although the application of this model probably resulted in an underestimated elimination half-life. This is not attributable to an inadequacy of the model in explaining the data, but simply to the fact that only 30 h of sampling were modeled in each subject, preventing a robust characterization of the true elimination half-life. This is in contrast to rich-sampling studies performed with this drug, where two- or three-compartment PK models were necessary to correctly characterize plasma concentrations and excreted urinary amounts (28) . In the present study, the one-compartment model explained the data just as well as a two- or three-compartment PK model. This is probably attributable to masking of the distribution phase by the long duration of the infusion and to underestimation of the "true" terminal elimination phase because of the limited number of plasma samples after the end of infusion. Nevertheless, the results of this PK analysis are very similar to the ones that have been reported in studies using more extensive sampling and a two- or three-compartment PK model. The CL was 1.73 liters/h/m2 versus the previously reported value of 1.63 liters/h/m2, the Vss was 12.72 liters/m2 versus 17.65 liters/m2, and the terminal elimination half-life was 7.13 h versus 12.3 h (27) . Some patients exhibited a PK profile that appeared to be different between the first and third dose administered; these patients were analyzed separately using a Bayesian algorithm. As mentioned before, these differences are probably the result of noisy data rather than a true inconsistency in the model. This is because although nonlinearity can exist with drugs in clearance processes, it is very rare to observe nonlinearity in the volumes of distribution.

In alternative schedules, DX-8951f has been given daily for 5 days, weekly for 3 of every 4 weeks, every 3 weeks, and as a continuous infusion over 5–21 days (23, 24, 25, 26, 27) . The daily for 5 days every 3 weeks schedule has been chosen for Phase II studies. This decision was based on preclinical models showing higher antitumor activity with cyclical dosing at lower doses compared with single-dose administration, antitumor activity observed with the daily for 5 days and weekly (30-min infusion) regimens, and less nausea and vomiting observed with the daily for 5 days regimen than with the weekly (30-min infusion) and single-dose (30-min infusion) schedules. There are no immediate plans to develop the present schedule for Phase II studies because of the inconvenience of administration of DX-8951f as a 24-h infusion and lack of superiority to the daily for 5 days schedule.

In conclusion, the recommended Phase II doses of DX-8951f given as weekly 24-h infusions 3 of every 4 weeks is 0.8 mg/m2 for minimally and 0.53 mg/m2 for heavily pretreated patients.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 To whom requests for reprints should be addressed, at Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Phone: (212) 639-8702; Fax: (212) 717-3320; E-mail: sharma1{at}mskcc.org Back

2 The abbreviations used are: CPT, camptothecin; Topo I, topoisomerase I; AUC, area under the curve; ANC, absolute neutrophil count; MTD, maximum tolerated dose; DLT, dose-limiting toxicity; HP, heavily pretreated; MP, minimally pretreated; PK, pharmacokinetic. Back

Received 2/14/01; revised 8/10/01; accepted 8/16/01.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Slichenmyer W. J., Rowinsky E. K., Donehower R. C., Kaufmann S. H. The current status of camptothecin analogues as antitumor agents. J. Natl. Cancer Inst., 85: 271-291, 1993.[Abstract/Free Full Text]
  2. Ikeda K., Terashima M., Yegashi Y., Kuboi M., Sasaki N., Kawamura H., Takiyama I., Maesawa C., Takagane A., Abe K., et al Antitumor activities of camptothecin analogues against human esophageal cancer. Proc. Am. Assoc. Cancer Res., 36: 453 1995.
  3. Mitsui I., Ohsuki S., Hirota Y., Sugimori M., Terasawa H., Sato K. High potency of a camptothecin derivative DX-8951 might be attributed to good membrane permeability. Proc. Am. Assoc. Cancer Res., 35: 455 1994.
  4. Mitsui I., Kumazawa E., Hirota Y., Aonuma M., Sugimori M., Ohsuki S., Uoto K., Ejima A., Terasawa H., Sato K. A new water-soluble camptothecin derivative, DX-8951f, exhibits potent antitumor activity against human tumors in vitro and in vivo. Jpn. J. Cancer Res., 86: 776-782, 1995.[CrossRef][Medline]
  5. Eckhardt S. G., Degen D., Tohgo A., Von Hoff D. Activity of DX-8951f, a water soluble camptothecin derivative, on primary human tumor colony-forming units. Proc. 9th NCI-EORTC Symp., : A447 1996.
  6. Weitman S., Degen M., Von Hoff D. Antitumor activity of topoisomerase I inhibitors against a pediatric solid tumor panel. Proc. Am. Assoc. Cancer Res., 37: 435 1996.
  7. Kumazawa E., Ochi Y., Nakayama Y., Iwahana M., Aonuma M., Tanaka N., Tohgo A. Antitumor effect of DX-8951f, a new camptothecin derivative in various murine models. Proc. Am. Assoc. Cancer Res., 36: 440 1995.
  8. Takiyama I., Terashima M., Ikeda K., Kawamura H., Sasaki N., Hayakawa Y., Ishida K., Saito K. Remarkable synergistic interaction between camptothecin analogs and cisplatin against human esophageal cancer cell lines. Proc. Am. Assoc. Cancer Res., 38: 15 1997.
  9. Takiguchi S., Kumazawa E., Shimazoe T., Tohgo A., Kono A. Antitumor effect of DX-8951, a novel camptothecin analog, on human pancreatic tumor cells and their CPT-11 resistant variants cultured in vitro and xenografted into nude mice. Jpn. J. Cancer Res., 88: 760-769, 1997.[CrossRef][Medline]
  10. Daiichi Pharmaceuticals. . DX-8951f clinical investigator’s brochure, Daiichi Fort Lee, NJ 1998.
  11. Kumazawa E., Jimbo T., Ochi Y., Tohgo A. Potent and broad antitumor effects of DX-8951f, a water-soluble camptothecin-derivative, against various human tumors xenografted into nude mice. Cancer Chemother. Pharmacol., 42: 210-220, 1998.[CrossRef][Medline]
  12. Gibaldi M., Perrier D. . Pharmacokinetics, Ed. 2 Marcel Dekker Inc. New York 1982.
  13. D’Argenio D. Z., Schumitzky A. A program package for simulation and parameter estimation in pharmacokinetic systems. Comput. Programs Biomed., 9: 115-134, 1979.[CrossRef][Medline]
  14. Gellert M. DNA topoisomerases. Annu. Rev. Biochem., 50: 879-910, 1981.[CrossRef][Medline]
  15. Giovanella B. C., Stehlin J. S., Wall M. E., Wani M. C., Nicholas A. W., Liu L. F., Silber R., Potmesil M. DNA topoisomerase I-targeted chemotherapy of human colon cancer in xenografts. Science (Wash. DC), 246: 1046-1048, 1989.[Abstract/Free Full Text]
  16. Kim R., Ohi Y., Inoue H., Toge T. Expression and relationship between topoisomerase I and II {alpha} genes in tumor and normal tissues in esophageal, gastric and colon cancers. Anticancer Res, 19: 5393-5398, 1999.[Medline]
  17. McLeod H. L., Douglas F., Oates M., Symonds R. P., Prakash D., Van Der Zee A. G., Kaye S. B., Brown R., Keith W. N. Topoisomerase I and II activity in human breast, cervix, lung and colon cancer. Int. J. Cancer, 59: 607-611, 1994.[Medline]
  18. Van Der Zee A. G., Hollema H., de Jong S., Boonstra H., Gouw A., Willemse P. H., Zijlstra J. G., De Vries E. G. P-Glycoprotein expression and DNA topoisomerase I and II activity in benign tumors of the ovary and in malignant tumors of the ovary, before and after platinum/cyclophosphamide chemotherapy. Cancer Res., 51: 5915-5920, 1991.[Abstract/Free Full Text]
  19. Gosky D. M., Belfi C. A., Dordal M. S., Berger N. A., Berger S. J. Topoisomerase I and II levels in human lymphoma cell lines SU-4 and SU-4R. Proc. Am. Assoc. Cancer Res., 38: 19 1997.
  20. Liu L. F. DNA topoisomerase poisons as antitumor drugs. Annu. Rev. Biochem., 58: 351-375, 1989.[CrossRef][Medline]
  21. Hsiang Y. H., Hertzberg R., Hecht S., Liu L. F. Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J. Biol. Chem., 260: 14873-14878, 1985.[Abstract/Free Full Text]
  22. Rothenberg M. L. Topoisomerase I inhibitors: review and update. Ann. Oncol., 8: 837-855, 1997.[Abstract/Free Full Text]
  23. Bates N. P., Boven E., Dobbs N., Varcoe S., Ruijter R., O’Grady J., Pinedo H. M., Talbot D. C. Phase I and pharmacokinetic study of DX-8951f, a novel topoisomerase inhibitor. Proc. Am. Soc. Clin. Oncol., 18: A684 1999.
  24. Geyer C., Hammond L. A., Johnson T., Smetzer L., Coyle J., Drengler R., Von Hoff D., De Jager R., Rowinsky E. Dose-schedule optimization of the hexacyclic camptothecin (CPT) analog DX-8951f: a Phase I and pharmacokinetic study with escalation of both treatment duration and dose. Proc. Am. Soc. Clin. Oncol., 18: A813 1999.
  25. Kamiya Y., Yamamoto N., Tamura T., Shimada Y., Oguma T. Phase I and pharmacokinetic (PK) study of DX-8951f, a novel camptothecin analog, given as 30 minute infusion daily for 5 days. Proc. Am. Soc. Clin. Oncol., 18: A832 1999.
  26. Minami H., Sasaki Y., Onozawa Y., Fujii H., Ohtsu T., Igarashi T., Itoh K., Tamanoi K., Oguma T. Phase I and clinical pharmacology of DX-8951f, a new camptothecin derivative, infused over 30 minutes every 3 weeks. Proc. Am. Soc. Clin. Oncol., 18: A685 1999.
  27. Royce M., Lassere Y., Hoff P., Brito R., Ravandi F., Medgysey D., Zukowski T., Coyle J., De Jager R., Pazdur R. DX-8951f: Phase I and pharmacokinetic study of a novel camptothecin analogue administered by 24-hour continuous infusion to patients with advanced solid tumors. Proc. Am. Soc. Clin. Oncol., 18: A682 1999.
  28. De Jager R., Cheverton P., Tamanoi K., Coyle J., Ducharme M., Sakamoto N., Satomi M., Suzuki M. DX-8951f: summary of Phase I clinical trials. Ann. NY Acad. Sci., 922: 260-273, 2000.[Abstract/Free Full Text]
  29. Chabot G. G., Abigerges D., Catimel G., Culine S., de Forni M., Extra J. M., Mahjoubi M., Herait P., Armand J. P., Bugat R. Population pharmacokinetics and pharmacodynamics of irinotecan (CPT-11) and active metabolite SN-38 during Phase I trials. Ann. Oncol, 6: 141-151, 1995.[Abstract/Free Full Text]
  30. Rothenberg M. L., Kuhn J. G., Burris H. A., III, Nelson J., Eckardt J. R., Tristan-Morales M., Hilsenbeck S. G., Weiss G. R., Smith L. S., Rodriguez G. I. Phase I and pharmacokinetic trial of weekly CPT-11. J. Clin. Oncol., 11: 2194-2204, 1993.[Abstract/Free Full Text]
  31. Rothenberg M. L., Eckardt J. R., Kuhn J. G., Burris H. A., III, Nelson J., Hilsenbeck S. G., Rodriguez G. I., Thurman A. M., Smith L. S., Eckhardt S. G., Weiss G. R., Elfring G. L., Rinaldi D. A., Schaaf L. J., Von Hoff D. D. Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. J. Clin. Oncol., 14: 1128-1135, 1996.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Clin. Cancer Res.Home page
O. Soepenberg, M. J. A. de Jonge, A. Sparreboom, P. de Bruin, F. A. L. M. Eskens, G. de Heus, J. Wanders, P. Cheverton, M. P. Ducharme, and J. Verweij
Phase I and Pharmacokinetic Study of DE-310 in Patients with Advanced Solid Tumors
Clin. Cancer Res., January 15, 2005; 11(2): 703 - 711.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
N. Masubuchi, R. D. May, and R. Atsumi
A Predictive Model of Human Myelotoxicity Using Five Camptothecin Derivatives and the In vitro Colony-Forming Unit Granulocyte/Macrophage Assay
Clin. Cancer Res., October 1, 2004; 10(19): 6722 - 6731.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
F. J. Giles, J. E. Cortes, D. A. Thomas, G. Garcia-Manero, S. Faderl, S. Jeha, R. L. De Jager, and H. M. Kantarjian
Phase I and Pharmacokinetic Study of DX-8951f (Exatecan Mesylate), a Hexacyclic Camptothecin, on a Daily-Times-Five Schedule in Patients with Advanced Leukemia
Clin. Cancer Res., July 1, 2002; 8(7): 2134 - 2141.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sharma, S.
Right arrow Articles by Saltz, L. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sharma, S.
Right arrow Articles by Saltz, L. B.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online