Japanese Journal of Clinical Oncology 30:377-384 (2000)
© 2000 Foundation for Promotion of Cancer Research
Pharmacokinetic and Pharmacodynamic Analysis of Bis-acetato-ammine-dichloro-cyclohexylamine-platinum(IV) (JM216) Administered Once a Day for Five Consecutive Days: A Phase I Study
,+ 1Thoracic Oncology Division, National Cancer Center Hospital, Tokyo, 2Division of Oncology and Hematology, National Cancer Center Hospital East, Kashiwa, Chiba, 3Department of Respiratory Medicine and Oncology, Osaka City General Hospital, Osaka and 4Fourth Department of Internal Medicine, Kinki University School of Medicine, Osaka, Japan
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Background: Bis-acetato-ammine-dichloro-cyclohexylamine-platinum(IV) (JM216) is the first orally given platinum complex that shows in vitro cytotoxicity comparable to that of cisplatin and in vivo cytotoxicity superior to those of cisplatin and carboplatin.
Methods: We conducted an escalating-dose (50, 75, 100, 120 mg/m2) phase I study of JM216 administered orally once a day for five consecutive days in patients with solid tumors to establish the toxicity profile, maximum tolerated dose (MTD) and pharmacokinetic profile. Twenty-three patients were enrolled and all were assessable for toxicity.
Results: The MTD was 120 mg/m2/day and the dose-limiting toxicities were leukopenia, thrombocytopenia, anemia and diarrhea. Because of the delayed hematological toxicities, it was difficult to repeat cycles every 26 days in some patients. Tumor shrinkage was observed in two patients with breast cancer, both of whom were resistant to doxorubicin. A pharmacokinetic study showed that the areas under the concentration–time curve (AUC) and peak plasma concentrations (Cmax) for total platinum (Pt) on days 1 and 5 and ultrafiltered Pt (UF-Pt) on day 1 increased in proportion to the dose of JM216. The AUCs for both total and UF-Pt on day 5 were higher than the AUCs on day 1. The AUC for UF-Pt on day 5 showed the best correlation with percentage reduction in leukocyte count and in absolute neutrophil count.
Conclusion: The recommended dose for phase II studies is 100 mg/m2/day every 4–6 weeks. The observation of tumor shrinkage in previously heavily treated breast cancer patients supports a phase II investigation.
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Since the successful introduction of cisplatin (cis-diammine-dichloro-platinum, CDDP) into clinical practice in the 1970s, CDDP has become one of the most potent cytotoxic agents prescribed and plays a key role in treating ovarian cancer, testicular cancer, non-small cell lung cancer (NSCLC), head and neck cancer and other malignancies. However, the clinical use of CDDP is often limited by several toxic reactions, such as nephrotoxicity, neurotoxicity and hearing impairment (1–3). JM216 (Fig. 1), bis-acetato-ammine-dichloro-cyclohexylamine-platinum(IV), administered orally, is a lipophilic platinum(IV) complex that has shown in vitro cytotoxicity comparable to that of CDDP and has overcome CDDP resistance in some cell lines (4). JM216 has also demonstrated efficacy superior to those of CDDP and carboplatin (cis-diammine-cyclobutane-dicarboxylato-platinum, CBDCA) in vivo (4). In preclinical studies in mice, the dose-limiting toxicity (DLT) of JM216 was myelosuppression and no nephrotoxicity or neurotoxicity was seen at the maximum tolerated dose (MTD) (5–7). Gastrointestinal toxicity was lower than that of CDDP (5). Recently, McKeage et al. reported a phase I trial of JM216 with single-dose administration (8). The doses were escalated from 60 to 700 mg/m2, but the study was stopped before reaching the MTD because of saturable pharmacokinetics. At dose levels >200 mg/m2, the peak plasma concentration (Cmax) and area under the concentration–time curve (AUC) of both total and ultrafiltered platinum (UF-Pt) became variable and reached a plateau. In vivo studies, on the other hand, showed schedule-dependent antitumor activity of JM216 (9) and suggested that a 5-day schedule was optimal for clinical use. We planned a phase I trial of JM216 administered orally once a day on five consecutive days to Japanese patients. The purpose of this study was to determine the MTD on this schedule, to determine the pharmacokinetic profile of this drug, especially protein-unbound platinum, and to observe any antitumor activity.
|
|
PATIENTS AND METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Eligibility
Patients with histologically or cytologically proven solid tumors that were refractory to standard therapy or for whom there was no effective therapy were enrolled. Eligibility criteria included age 20–74 years, ECOG performance status (PS) 0–2, life expectancy >2 months, adequate organ function (4000/mm3
white blood cell (WBC) counts < 10 000/mm3, platelet counts (plt) 
100 000/mm3, hemoglobin level 9.5 g/dl, total bilirubin level 1.5 mg/dl, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) level 2.5 times their upper normal limit, serum creatinine 1.3 mg/dl, blood urea nitrogen 25 mg/dl and creatinine clearance 60 ml/min). Patients were treated on an inpatient basis. At least 4 weeks (6 weeks in the case of nitrosourea, CBDCA and mitomycin) must have passed after the completion of previous therapy and the patients had to have recovered from the toxic effects of previous therapy. Exclusion criteria consisted of severe heart disease, cerebrovascular disease, uncontrollable diabetes mellitus, uncontrollable hypertension, severe infection, massive pleural effusion or ascites, active peptic ulcer, active concurrent malignancies, brain metastasis, pregnancy, lactation and use of corticosteroids. Patients who had a history of gastrointestinal disorders that might affect absorption (e.g. total gastrectomy) or who had experienced severe uncontrollable emesis from previous platinum-based chemotherapy were excluded. Prior wide-field irradiation, e.g. greater than half of the pelvic bone, also made patients ineligible. This study was performed at the National Cancer Center Hospital, the National Cancer Center Hospital East and the Osaka City General Hospital and was approved by the Institutional Review Board of each institution. Written informed consent was obtained from all patients. This study was conducted in accordance with Japanese Good Clinical Practice (GCP). Central registration with the Department of Health Science, Faculty of Medicine, University of Tokyo by facsimile was employed.
Pretreatment and Follow-up Studies
Prior to entry, a complete history and physical examination that included height, weight, performance status and clinical stage were performed. Pretreatment laboratory studies included a complete blood cell count, differential leukocyte count, platelet count, serum electrolytes, total protein, albumin, total bilirubin, total cholesterol, alkaline phosphatase, AST, ALT, lactate dehydrogenase, blood urea nitrogen, creatinine, creatinine clearance by 24 h urine collection as a substitute for chromium-51-edathamil (51Cr-EDTA) clearance because of limited availability, coagulation studies and urinalysis. These studies were repeated on days 6 and 12 and weekly thereafter. A chest X-ray was performed before treatment and on day 26 and an ECG was performed before treatment and on days 6 and 26. Toxicities were evaluated according to Japan Clinical Oncology Group (JCOG) toxicity criteria (10), which are an expanded version of the National Cancer Institute Common Toxicity Criteria (NCI-CTC). Tumor response was assessed by using the standard response criteria. A ‘complete response’ (CR) required complete disappearance of all clinical evidence of disease for at least 4 weeks. A ‘partial response’ (PR) required a 50% decrease in the sum of the products of the perpendicular diameters of all measured lesions that persisted for at least 4 weeks. ‘Progression disease’ (PD) was defined as any increase of 25% in the products of the perpendicular diameters of any measured lesion or the appearance of a new lesion on any imaging study. The remaining patients were evaluated as ‘no change’ (NC).
Drug Administration and Dose Escalation
JM216 was supplied as 10 and 50 mg hard gelatin capsules containing excipients (microcrystalline cellulose, sodium starch glycolate, lactose anhydrous and magnesium stearate) by Bristol-Myers Squibb (Tokyo, Japan). The drug was stored in light-resistant packaging at room temperature. JM216 was given orally with 200 ml of water once a day in the morning for five consecutive days. Patients fasted from 22:00 to 12:00 and were allowed to take only fluids between 09:00, when JM216 was administered, and 12:00. A prophylactic antiemetic, 4 mg of ondansetron, was given orally 1 h before administration of JM216.
The starting dose of JM216 was 50 mg/m2. This dose was chosen based on the study by McKeage et al. using this schedule in which the recommended dose for previously treated patients was 100 mg/m2 and toxicity was mild at the 60 mg/m2 level (9). The dose escalation levels used were 50, 75, 100 and 120 mg/m2. At least three patients were treated at each dose level. Three additional patients were entered at the same dose level if DLT was observed in one or two of the first three patients. The MTD was defined as the dose level at which three of the three to six patients experienced DLT during their first course. The definition of DLT was as follows: (1) grade 4 neutropenia, (2) grade 3 leukopenia, thrombocytopenia or anemia, (3) grade 3 diarrhea, neurotoxicity or bilirubin elevation and (4) grade 2 other non-hematological toxicity (except nausea, vomiting, alopecia) by JCOG toxicity criteria. Intra-patient dose escalation was not allowed. Treatment was repeated every 26 days, for a maximum of four courses.
Patients with clear evidence of disease progression were removed from the study. When more than one course was given, the next course was started after recovery from the toxic effects of the previous course. If patients experienced DLT during the initial course, dose reduction to the previous dose level was allowed in the next course.
Pharmacokinetics
Pharmacokinetic studies were performed in all patients in the first course. Heparinized venous blood samples (5 ml) were taken to obtain plasma before administration and at 0.5, 1, 1.5, 2.0, 3.0, 4.0, 6.0 and 8.0 h after the initial dose on day 1, immediately prior to the second to fourth dose on days 2–4 and before administration and at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 24, 96, 168, 336 and 504 h after the fifth dose on day 5. The clock-time of acquisition of each sample was recorded. Blood samples were immediately centrifuged (2000 g for 5 min at 4°C) after collection to obtain plasma and aliquots (2x0.5 ml) were placed in serum tubes for plasma total platinum analysis and stored at –80°C. Plasma ultrafiltrate samples were immediately prepared from the remaining plasma by using four Amicon Centrifree filters (30 000 MW cutoff) (Amicon Division, W.R. Grace, Beverly, MA, USA) per sample. The filters were centrifuged (2000 g for 15 min at 4°C) and stored at –80°C. Urine samples were collected during intervals of 0–8 and 8–24 h after administration on day 1 and 0–24 h on days 2–5. Urine was collected in a container and the total volume was recorded. The platinum concentrations in plasma, plasma ultrafiltrate and urine were determined by flameless atomic absorption spectrometry (AAS) using a Hitachi polarized Zeeman spectrophotometer (Model Z-8200). A 100 µl aliquot of the plasma sample was mixed with 300 µl of 0.5% Triton X-100 in an autosampler sample cup. A 100 µl aliquot of a UF sample was mixed with 20 µl of 2% Triton X-100 in a sample cup. Plasma concentrations of metabolites were not measured in this study. Urine samples were diluted 10-fold by mixing 0.5 ml aliquots of urine and 4.5 ml of 0.05% Triton X-100. A 1 ml aliquot of the diluted urine was transferred to a sample cup and 20 µl aliquots of the processed samples were analyzed in duplicate by graphite furnace atomic absorption spectrometry using Zeeman-effect background correction. The samples were dried at 75–120°C, ashed at 1400°C and atomized at 2600°C. The peak absorption at 265.9 nm was measured and platinum concentrations were calculated from an external calibration curve. The lower limits of quantitation (LOQ) for platinum in plasma, UF and urine were 30, 10 and 100 ng Pt/ml, respectively. Calibration curves were linear over concentration ranges of 30–1000, 10–200 and 100-4000 ng Pt/ml in plasma, UF and urine, respectively. This method was based on the assay method for CDDP in biological fluids established by Adnan and Iman (11)
The pharmacokinetic parameters, AUC0–24 h and the apparent elimination half-life (t) were obtained from the platinum concentrations in plasma and plasma ultrafiltrate by a non-compartmental moment method (12) The Cmax was the actually observed peak concentration. The AUC0–24 h was calculated by the trapezoidal rule. The terminal slope of the plasma, the plasma ultrafiltrate log(concentration) versus time curve and elimination rate constant (ß) were determined by least-squares linear regression analysis using more than three points at and before 24 h after oral administration. t was calculated by using the equation t = ln(2)/ß. The t of total platinum in plasma was also calculated from 96 to 504 h after the fifth dose.
Pharmacodynamic correlations between the AUCs and the percentage changes in the WBC count, absolute neutrophil count (ANC) and platelet count were tested by linear regression analysis. The percentage change was calculated as [(pretreatment blood count – nadir blood count)x100]/pretreatment blood count.
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Between April 1995 and November 1996, a total of 23 patients were enrolled. The total and the median number of courses were 36 and 1 (range 1–4), respectively. The patient characteristics are shown in Table 1. Most patients had good performance status (PS 0/1, 21 pts; PS 2, 2 pts). The most common tumor types were NSCLC, breast cancer and head and neck cancer. There were three previously untreated patients and 20 previously treated patients. Of the previously treated patients, 19 had received prior chemotherapy, with a median of one regimen (range 1–4), and nine had received platinum-based chemotherapy (CDDP, 8 pts; CBDCA, 1 pt).
|
Toxicities
All patients were assessable for toxicity. The numbers of patients given each dose level are shown in Table 2 and the hematological and non-hematological toxicities observed after the first course are detailed in Tables 2 and 3, respectively. At level 1 (50 mg/m2), both hematological and non-hematological toxicities were generally mild. In one patient, a transient grade 1 visual abnormality was observed on day 6. At level 2 (75 mg/m2), one patient received the incorrect dosage (63 mg/m2) on day 1 because of a mistake in calculating it and experienced grade 2 transaminase elevation and grade 2 diarrhea. Another heavily pretreated patient experienced grade 3 leukopenia, grade 3 thrombocytopenia and grade 2 fever. At level 3 (100 mg/m2), one heavily pretreated patient experienced grade 3 thrombocytopenia, grade 3 anemia, grade 4 diarrhea and grade 2 fever. At level 4 (120 mg/m2), one head and neck cancer patient took JM216 only on days 1 and 3–6, because he forgot to take it on day 2. He experienced grade 3 leukopenia, grade 3 thrombocytopenia and grade 3 anemia. Another previously untreated patient experienced grade 3 hypotension, grade 3 infection and grade 3 thrombocytopenia. Two other patients also had DLT, grade 3 leukopenia in one and grade 3 diarrhea in the other.
|
|
Accordingly, this dose level, 120 mg/m2/day, was determined to be the MTD and it was decided that 100 mg/m2/day should be the recommended dose. Overall major toxicities following all courses are listed in Table 4. None of the patients developed grade 4 myelosuppression. Grade 3 leukopenia was observed in three patients, grade 3 thrombocytopenia in four and grade 3 anemia in four. The median leukocyte nadirs occurred on day 32 (range 4–56) and recovery occurred on day 40 (range 14–51). The median thrombocyte and hemoglobin nadirs occurred on day 25 and day 26, respectively, and recovery occurred on day 32 and day 37.5, respectively. Non-hematological toxicities were generally mild. Two patients developed more than grade 3 diarrhea and 13 patients (20 courses) developed grade 1 or 2 diarrhea. This toxicity occurred on day 2 (median, range 1–10), with a median recovery time of 4 days (range 2–18). The diarrhea could be controlled with loperamide. There was no grade 3 or 4 nausea/vomiting and 19 patients (25 courses) developed grade 1 or 2 nausea/vomiting. No vomiting occurred within 3 h after administration of JM216. Eight patients (10 courses) developed grade 1 or 2 fever. These toxicities occurred on day 5 (median, range 1–7). The relationship between the fever and JM216 was unclear. Nephrotoxicity and neurotoxicity were rare.
|
There was no cumulative toxicity in any of the patients despite the prolonged hematological toxicities.
Pharmacokinetics and Pharmacodynamics
Pharmacokinetic studies were carried out and analyzed in 21 patients. The pharmacokinetic parameters are listed in Table 5 and the mean platinum concentration–time profiles are shown in Fig. 2. The total Pt concentrations peaked at 3–6 h after administration, whereas the peak concentrations of UF-Pt occurred at 1.5–3 h. The AUCs for both total and UF-Pt on day 5 were significantly higher than on day 1. The AUC and Cmax for total Pt on both days 1 and 5 increased in proportion to the dose of JM216 (AUC day 1 r = 0.83, day 5 r = 0.62, Cmax day 1 r = 0.80, day 5 r = 0.61), suggesting linear pharmacokinetics in this dose range. The AUCs for UF-Pt on day 1 increased proportionally (r = 0.72), but the AUCs for UF-Pt on day 5 were widely distributed (r = 0.36) (Fig. 3). The cumulative excretion of Pt in the urine for 5 days after administration was 11.1% (mean value) at 50 mg/m2, 7.8% at 75 mg/m2, 8.1% at 100 mg/m2 and 6.1% at 120 mg/m2.
|
|
|
Table 6 shows the correlations between the pharmacokinetic parameters (total AUC and UF on days 1 and 5) and the percentage change in hematological toxicities. The AUC for UF-Pt on day 5 correlated with the percentage reduction in WBC count (r = 0.67) and somewhat better with the percentage reduction in ANC (r = 0.70) than for total Pt (r = 0.44–0.47) and UF-Pt on day 1 (r = 0.29 and 0.36) (Fig. 4).
|
|
Clinical Response
Of the 23 patients, 22 were assessed for response. No objective response was seen, but tumor shrinkage that did not meet the response criteria was observed in two breast cancer patients. One was a 44-year-old woman with breast cancer previously treated with chemotherapy (5FU and six cycles of cyclophosphamide, adriamycin, 5FU) and radiotherapy at level 2. Her metastatic neck lymph nodes were undetectable after one cycle of JM216, but the response duration was only 12 days. The other was a 44-year-old woman with breast cancer previously treated with chemotherapy (UFT, tegafur and three cycles of taxotere, adriamycin) at level 3 and 30% regression of metastatic supraclavicular lymph nodes for more than 2 months was observed.
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
JM216, the first orally administered platinum drug, is currently undergoing clinical trials (8,13,14). It had demonstrated a therapeutic index superior to that of CDDP and CBDCA in vivo and partial non-cross resistance to these agents in vitro.
In 1995, McKeage et al. reported the first phase I study (8) of JM216 by single dose administration. In that study, no DLT was seen in the dose range from 60 to 700 mg/m2 and the pharmacokinetic study revealed that absorption was saturable at doses >200 mg/m2. In vivo studies, on the other hand, showed JM216 to have schedule-dependent antitumor activity and suggested that the 5-day schedule was optimal (9) for clinical use. McKeage et al. conducted the second phase I study using a 5-day schedule and reported a recommended dose of 100 mg/m2/day for previously treated patients and of 120 mg/m2/day for untreated patients (13). Based on this evidence, we initiated the second phase I study of this drug with the 5-day schedule for Japanese patients and reported an MTD and a recommended dose for the phase II study of 120 and 100 mg/m2/day, respectively. Although the toxicity profile was slightly different from that reported by McKeage et al. (13), the results of our study with Japanese patients agreed with those of their previous study, because in our study most patients had been treated previously.
The DLTs in this study were leukopenia, thrombocytopenia, anemia and diarrhea. Hematological toxicities tended to be prolonged. The median leukocyte nadirs occurred on day 32 and recovery occurred on day 40. The median thrombocyte and hemoglobin nadirs also occurred on days 25 and 26 and recovery occurred on days 32 and 37.5, respectively. Initially we planned to repeat the course every 26 days, but that was difficult in some patients because of the prolonged hematological toxicities. Although the report of McKeage et al. (13) suggested that recovery from hematological toxicities allowed repeat courses to be given to most patients by 28 days, our study suggested that the optimal interval for JM216 administration on the 5-day schedule is 4–6 weeks. However, further studies are necessary to evaluate whether decreasing the delivered dose intensity of JM216 is a clinical disadvantage.
Diarrhea was one of the DLTs in the present study. McKeage et al. reported that mild diarrhea was observed in 48% of a total of 92 courses (13) and was usually of grade 1 severity. In our study, there was grade 4 diarrhea in one patient, grade 3 diarrhea in one patient and grade 1 or 2 in 13 patients. The median time of onset of diarrhea was day 2 (range 1–10) and the median duration was 4 days (range 2–18). The diarrhea could be controlled by oral loperamide in most patients.
A prophylactic antiemetic, ondansetron, was employed in this study and there was no grade 3 emesis. McKeage et al. (13) reported that vomiting was a common toxicity (92% of total courses) without antiemetics in their first phase I study and was mostly of grade 2 severity, whereas vomiting occurred in 52% of the courses in the second phase I study, with antiemetics and was generally of grade 1 severity. Although antiemetics can decrease the severity of nausea and vomiting, it will be necessary to examine whether antiemetics inhibit absorption of JM216 or alter its pharmacokinetics.
Pharmacokinetic studies have shown that the AUC and Cmax of both total Pt and UF-Pt increased with the dose and that absorption was not saturable in this dose range. The evidence that the AUCs and Cmax on day 5 were higher than on day 1 also suggested drug accumulation. Cumulative excretion in the urine was small. Calvert et al. suggested that the dose-limiting thrombocytopenia of CBDCA is strongly correlated with the AUC of the UF plasma concentration (15) It appears to be important to measure the protein-unbound fraction of the drug. The AUCs for UF-Pt on day 1 increased in proportion to the dose, whereas those on day 5 were distributed widely and there was no significant correlation between the AUCs for UF-Pt on day 1 and day 5. The variability on day 5 may be partly attributable to interindividual variability and partly to the low correlation between JM216 dosage and the AUCs for UF-Pt as a result of increasing the platinum concentration because of accumulation. McKeage et al. reported that the severity of thrombocytopenia was significantly associated with the sum of the day 1 and day 5 AUCs of UF-Pt based on a sigmoidal model (13). Our pharmacokinetic and pharmacodynamic study, on the other hand, showed a better correlation between the AUC for UF-Pt on day 5 and the percentage reduction in WBC and neutrophil count. We used the linear regression analysis for this analysis, because the values of the AUCs of UF-Pt on day 5 were very small and their range was narrow (0.238–0.922 µg.h/ml) in the dose range from 50 to 120 mg/m2/day. Moreover, even when using the sigmoidal model, the relationships between the AUCs of UF-Pt on day 5 and percentage reduction in WBC and neutrophil counts was almost identical with the initial linear portion of the sigmoidal model. Therefore, since the percentage reduction in WBC and neutrophils increased in proportion to the AUCs of UF-Pt on day 5, it is possible to predict the WBC or neutrophil nadirs from the AUC range (0.238–0.922 µg.h/ml). Ideally, if clinical efficacy and/or toxicity could be predicted on the basis of the pharmacokinetic parameters, especially on day 1, it would be possible to adapt the control dosage of JM216, but we were unable to define the relationship.
Raynaud et al. recently reported finding complete conversion of JM216 into at least six metabolites in plasma ultrafiltrates of 12 patients as early as 20 min post-administration, with no parent JM216 detected in the patients’ plasma ultrafiltrates. Four of the metabolites, Pt(II), JM118 and Pt(IV), JM383 were identified as active metabolites (16). We did not measure metabolites in our study because the assay methods for the active metabolites are still being developed. In future trials of JM216, the relationship between the parameters of these active metabolites and pharmacodynamic effects and the factors that contribute to the wide variability should be evaluated.
Although there was no objective response in this study, two of the four breast cancer patients experienced tumor shrinkage. Since both patients were previously heavily treated, further evaluation is warranted for breast cancer.
In summary, the MTD of JM216 is 120 mg/m2/day and the recommended dose for phase II studies is 100 mg/m2/day every 4–6 weeks. The dose-limiting toxicities are myelosuppression (leukopenia, thrombocytopenia, anemia) and diarrhea.
|
FOOTNOTES |
|---|
+ For reprints and all correspondence : Takayasu Kurata, Thoracic Oncology Division, National Cancer Center Hospital, 1–1, Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, JapanAbbreviations: MTD, maximum tolerated dose; AUC, area under concentration–time curve; Cmax, peak plasma concentration; Pt, total platinum; UF-Pt, ultrafiltered platinum; CDDP, cis-diammine-dichloro-platinum; CBDCA, cis-diammine-cyclobutane-dicarboxylato-platinum; DLT, dose-limiting toxicity; PS, performance status; WBC, white blood cell; plt, platelet count; AST, aspartate aminotransferase; ALT, alanine aminotransferase; GCP, Good Clinical Practice; 51Cr-EDTA, chromium-51-edathamil; JCOG, Japan Clinical Oncology Group; NCI-CTC, National Cancer Institute Common Toxicity Criteria; CR, complete response; PR, partial response; NC, no change; PD, progression disease; AAS, atomic absorption spectrometry; LOQ, lower limit of quantitation; t, half-life; ANC, absolute neutrophil count; NSCLC, non-small cell lung cancer; pt, patient; BRM, biological response modifier; SD, standard deviation
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
1 Goren MP, Wright RK, Horowitz ME. Cumulative renal tubular damage associated with cisplatin nephrotoxicity. Cancer Chemother Pharmacol 1986;18:69–73.[Web of Science][Medline]
2 Legha SS, Dimery IW. High-dose cisplatin administration without hypertonic saline: observation of disabling neurotoxicity. J Clin Oncol 1985;3:1373–8.
3 Schaefer SD, Post JD, Close LG, Wright CG. Ototoxicity of low- and moderate-dose cisplatin. Cancer 1985;56:1934–9.[Web of Science][Medline]
4 Kelland LR, Abel G, McKeage MJ, Jones M, Goddard PM, Valenti M, et al. Preclinical antitumor evaluation of bis-acetato-ammine-dichloro-cyclohexylamine platinum (IV): an orally active platinum drug. Cancer Res 1993;53:2581–6.
5 McKeage MJ, Morgan SE, Boxall FE, Murrer BA, Hard GC, Harrap KR. Preclinical toxicology and tissue platinum distribution of novel oral antitumor platinum complexes: ammine/amine platinum (IV) dicarboxylates. Cancer Chemother Pharmacol 1994;33:497–503.[Web of Science][Medline]
6 McKeage MJ, Morgan SE, Boxall FE, Murrer BA, Hard GC, Harrap KR. Lack of nephrotoxicity of oral ammine/amine platinum (IV) dicarboxylate complexes in rodents. Br J Cancer 1993;67:996–1000.[Web of Science][Medline]
7 McKeage MJ, Boxall FE, Jones M, Harrap KR. Lack of neurotoxicity of oral bisacetatoamminedichloro-cyclohexylamine-platinum [IV] in comparison to cisplatin and tetraplatin in the rat. Cancer Res 1994;54:629–31.
8 McKeage MJ, Mistry P, Ward J, Boxall FE, Loh S, O’Neill C, et al. A phase I and pharmacology study of an oral platinum complex, JM216: dose-dependent pharmacokinetics with single-dose administration. Cancer Chemother Pharmacol 1995;36:451–8.[Web of Science][Medline]
9 McKeage MJ, Kelland LR, Boxall FE, Valenti MR, Jones M, Goddard PM, et al. Schedule dependency of orally administered bis-acetato-ammine-dichloro-cyclohexylamine-platinum (IV) (JM216) in vivo. Cancer Res 1994;54:4118–22.
10 Tobinai K, Kohno A, Shimada Y, Watanabe T, Tamura T, Takeyama K, et al. and members of the Clinical Trial Review Committee of the Japan Clinical Oncology Group. Toxicity grading criteria of the Japan Clinical Oncology Group. Jpn J Clin Oncol 1993;23:250–7.
11 Adnan E-Y, Iman A-S. Rapid determination of platinum by flameless atomic absorption spectrometry following the administration of cisplatin to cancer patients. Ther Drug Monit 1986;8:318–20.[Web of Science][Medline]
12 Yamaoka K, Nakagawa T, Uno T. Statistical moments in pharmacokinetics. J Pharmacokinet Biopharm 1978;6:547–8.[Web of Science][Medline]
13 McKeage MJ, Raynaud F, Ward J, Berry C, O’Dell D, Kelland LR, et al. Phase I and pharmacokinetic study of an oral platinum complex given daily for 5 days in patients with cancer. J Clin Oncol 1997;15:2691–700.
14 Beale P, Raynaud F, Hanwell J, Berry C, Moore S, Odell D, et al. Phase I study of oral JM216 given twice daily. Cancer Chemother Pharmacol 1998;42:142–8.[Web of Science][Medline]
15 Calvert AH, Newell DR, Gumbrell LA, O’Reilly S, Burnell M, Boxall FE, et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol 1989;7:1748–56.[Abstract]
16 Raynaud FI, Mistry P, Donaghue A, Poon GK, Kelland LR, Barnard CFJ, et al. Biotransformation of the platinum drug JM216 following oral administration to cancer patients. Cancer Chemother Pharmacol 1996;38:155–62.[Web of Science][Medline]
Received April 21, 2000; accepted June 26, 2000.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  A. D. Ricart, J. Sarantopoulos, E. Calvo, Q. S. Chu, D. Greene, F. E. Nathan, M. E. Petrone, A. W. Tolcher, and K. P. Papadopoulos Satraplatin, an Oral Platinum, Administered on a Five-day Every-Five-Week Schedule: a Pharmacokinetic and Food Effect Study Clin. Cancer Res., June 1, 2009; 15(11): 3866 - 3871. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Choy, C. Park, and M. Yao Current Status and Future Prospects for Satraplatin, an Oral Platinum Analogue Clin. Cancer Res., March 15, 2008; 14(6): 1633 - 1638. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. R. Berthold, C. N. Sternberg, and I. F. Tannock Management of Advanced Prostate Cancer After First-Line Chemotherapy J. Clin. Oncol., November 10, 2005; 23(32): 8247 - 8252. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||