|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2000 American Society for Clinical Oncology Phase I and Pharmacologic Study of Docetaxel and Irinotecan in Advanced Non–Small-Cell Lung CancerFrom the Departments of Internal Medicine, Osaka Prefectural Habikino Hospital and Kinki University School of Medicine; Department of Respiratory Disease, Osaka City General Hospital; 1st Department of Internal Medicine, Osaka City University School of Medicine, Osaka; Department of Respiratory Disease, Aichi Cancer Center, and 1st Department of Internal Medicine, Nagoya University, School of Medicine, Aichi; and The Tokyo Cooperative Oncology Group, Tokyo, Japan. Address reprint requests to Noriyuki Masuda, MD, PhD, Department of Internal Medicine, Osaka Prefectural Habikino Hospital, 3–7-1 Habikino, Habikino Osaka 583-8588, Japan.
PURPOSE: We conducted a phase I trial of docetaxel, a new antimicrotubule agent, combined with irinotecan (CPT-11), a topoisomerase I inhibitor. The aim was to determine the maximum-tolerated dose (MTD) of docetaxel combined with CPT-11, as well as the dose-limiting toxicities (DLTs) of this combination in advanced non–small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Thirty-two patients with stage IIIB or IV NSCLC were treated at 4-week intervals with docetaxel (60 minutes, day 2) plus CPT-11 (90 minutes, days 1, 8, and 15). The starting doses of docetaxel/CPT-11 were 30/40 mg/m2, and doses were escalated in 10-mg/m2 increments until the MTD was reached. RESULTS: The MTD of docetaxel/CPT-11 was 50/60 mg/m2 (level 5A), or 60/50 mg/m2 (level 5B). Neutropenia and diarrhea were the DLTs. CPT-11 did not affect the pharmacokinetics of docetaxel. There were 11 (37%) partial responses among 30 patients. The median survival time was 48 weeks, and the 1-year survival rate was 44.9%. CONCLUSION: The combination of docetaxel and CPT-11 seems to be active against NSCLC, with acceptable toxicity. The recommended dose for phase II studies is 50 mg/m2 of CPT-11 (days 1, 8, and 15) and 50 mg/m2 of docetaxel (day 2) administered every 28 days.
DOCETAXEL IS A semisynthetic taxoid prepared from the noncytotoxic precursor 10-deacetyl baccatin III, which is extracted from the needles of the European yew, Taxus baccata. It promotes tubulin assembly into microtubules and inhibits depolymerization to free tubulin, thus blocking cells in the M-phase of the cell cycle.1,2 In preclinical studies, docetaxel demonstrated high antitumor activity against multiple murine transplantable tumors, as well as against human tumor xenografts.3-6 The pooled major response rate to docetaxel at 100 mg/m2 in chemotherapy-naive patients with advanced or metastatic non–small-cell lung cancer (NSCLC) was 29% on an intent-to-treat analysis.7 Irinotecan (CPT-11) is a water-soluble camptothecin derivative that inhibits topoisomerase I by stabilizing the enzyme-DNA cleavable complex and thus causes single-strand DNA breaks. CPT-11 has shown significant antitumor activity against various animal and human malignancies, including lung cancer.8-16 Preclinical studies17 have demonstrated that the sequential administration of docetaxel and CPT-11 in vitro resulted in at least supra-additive cytotoxicity for human lung cancer cell lines and that the order of administration did not seem to matter. In contrast, antagonism was observed when both drugs were simultaneously applied to human lung cancer cells. On the basis of the different cellular targets and action at different phases of the cell cycle (S phase for CPT-11 and mitosis for docetaxel), the single-agent activity of docetaxel and CPT-11 in patients with NSCLC, and the results of the preclinical studies showing the potentiation of single-agent activity with sequential administration of both drugs, a combination phase I trial in patients with advanced NSCLC was carried out. The objectives of this phase I study were as follows: to determine the maximum-tolerated dose (MTD) of docetaxel and CPT-11; to detect and quantify the clinical toxicities of this combination; to investigate the pharmacokinetics of docetaxel, CPT-11, and the CPT-11 active metabolite, SN-38; and to obtain preliminary evidence of the therapeutic activity of this combination in patients with advanced NSCLC.
Patient Selection Patients were enrolled onto this study if they met the following criteria: a histologic or cytologic diagnosis of lung cancer; a stage IV disease, or stage IIIB disease that was not a candidate for curative radiation therapy; a measurable or assessable lesion; no prior therapy; a performance status of 0, 1, or 2 on the Eastern Cooperative Oncology Group (ECOG) scale; a life expectancy of at least 3 months; adequate bone marrow function (leukocyte count  4,000/µL, neutrophil count 12,000/µL, platelet count 100,000/µL, and hemoglobin level 9.5 g/dL), adequate hepatic function (AST and ALT levels  2.0 times the upper limit of normal, and bilirubin level the upper limit of normal), adequate renal function (creatinine level the upper limit of normal, 24-hour creatinine clearance 50 mL/min), and arterial oxygen partial pressure of 70 torr or greater; age between 20 and 74 years; and written informed consent to the study. Patients were ineligible if they experienced the following: had serious infectious diseases or other severe complications (heart diseases, pulmonary fibrosis/interstitial pneumonia, bleeding, uncontrollable diabetes, or pseudomembranous colitis); had symptomatic peripheral neuropathy; had watery diarrhea, paralytic ileus, or intestinal obstruction; had massive pleural effusion or ascitic fluid; had symptomatic brain metastases; had active concurrent malignancies; were lactating or pregnant women, or were willing to be pregnant; had a history of a drug allergy; had a history of acute myocardial infarction within the previous 6 months; had superior vena caval syndrome, which required urgent radiotherapy; or had other medical problems severe enough to prevent compliance with the protocol. Patients currently being treated with calcium channel blockers, ketoconazol, erythromycin, or systemic corticosteroid therapy were also ineligible. The study was approved in advance by the Institutional Review Board and by the Hospital Ethics Committee.
Drug Administration CPT-11 was obtained as 5-mL vials containing 100 mg of the drug and was diluted in 500 mL of normal saline for administration, then administered to the patient as a 90-minute intravenous infusion on days 1, 8, and 15. The regimen was repeated every 28 days. CPT-11 treatment was terminated if the patient’s leukocyte count was less than 2,000/µL, platelet count was less than 50, 000/µL, fever was greater than 38°C, or if grade 1 or higher diarrhea occurred on the day when the dose was due. According to the revision of the administration method of CPT-11 (recommendation from the Ministry of Health and Welfare), the protocol was amended for dose level 5B as follows: during the course of the treatment, the dose of CPT-11 was withheld in instances in which the leukocyte count was less than 3,000/µL, platelet count was less than 100, 000/µL, fever greater than 37.5°C was present, or if grade 1 or higher diarrhea occurred on the day when the dose was due.
Dosage and Dose-Escalation Procedure The MTD was defined as the dose level at which at least three of the six patients (or all of the three patients, if only three were treated at a dose level) developed the DLT during course 1 therapy. No intrapatient dose escalation was allowed in this trial. Patients who were stabilized or who improved received at least a second course of treatment. Patients with obvious evidence of disease progression or those who experienced intolerable toxicity were removed from the study. If more than 6 weeks had passed since the time of the last treatment, patients were also removed from the study. Before the next course was started, the WBC count had to be 4,000/µL or higher, neutrophil count had to be 2,000/µL or higher, the platelet count had to be 100,000/µL or higher, the serum bilirubin level had to be less than the upper limit of normal, transaminase levels had to be less than twice the normal upper limit, and diarrhea should have completely resolved.
Evaluation
Pharmacokinetics
Pharmacokinetic Analyses
Between July 1995 and May 1998, 32 patients participated in this trial. A profile of the patient population is given in Table 1. Eleven patients were women, and 21 were men, and the median age was 56 years (range, 43 to 71 years) with a median performance status of 1. Dosing information is listed in Table 2. In this study, a total of 74 courses of therapy was given. The number of treatment cycles administered per patient ranged from 1 to 5 (one cycle in eight patients, two in 13, three in five, four in five, and five in one patient).
Toxicity Thirty patients were fully assessable for toxicity. One patient at dose level 1 was ineligible because he was undergoing nifedipine therapy for hypertension. One patient at dose level 2 suffered from hypotension during the infusion of docetaxel on day 2. The docetaxel was immediately discontinued, the patient was treated for a presumed acute hypersensitivity reaction, and his symptoms were reversed. He was removed from the study. Details of the percentage of CPT-11 doses actually delivered against the planned doses at each dose level are also given in Table 2. Dose omissions of CPT-11 on day 8 or 15 were mainly a result of diarrhea and/or leukopenia. The percentage of the scheduled dose actually administered was relatively high until dose level 3. The DLTs observed during the first course of treatment were neutropenia, neutropenic fever, diarrhea, and liver dysfunction (Table 3). The most frequent DLT of this combination regimen was diarrhea. Although there was no grade 2 or worse diarrhea at the first dose level, eight occasions of grade 2 or worse diarrhea were noted from the second dose level. At dose levels 2, 3, and 4, the first course caused diarrhea in 17% of the patients at each dose level, and the rate increased to 33% at dose level 5A. Furthermore, all three patients treated at dose level 5B developed grade 2 diarrhea, and two of three episodes were associated with asymptomatic grade 4 neutropenia or febrile neutropenia.
Although there was no grade 4 neutropenia for 3 days or more at dose levels 1 and 2, a trend toward increased severity with higher dose levels was evident (Table 3). Grade 4 neutropenia 3 days or febrile neutropenia occurred in 17% of the patients at dose levels 3 and 4, in 33% at dose level 5A, and in 67% at dose level 5B (Table 3). Two (33%) of six episodes of neutropenia were asymptomatic, whereas two (33%) were associated with diarrhea, and two (33%) occurred coincidentally with diarrhea and fever (one in dose level 4 and one in dose level 5B). This trial was closed at dose level 5B because the high frequency of DLTs, especially diarrhea, clearly precluded a further increase of the dose of each drug. Table 4 shows the maximum toxicities experienced during the treatment. The most frequent toxicities were leukopenia and neutropenia. The median time to neutrophil nadir for patients who experienced neutropenia during the first course (n = 14) was 13 days, with the median time to recovery being 6 days. Other toxicities of grade 2 or higher were anemia (44%) and thrombocytopenia (3%). Nonhematologic toxicities of grade 2 or worse included nausea and vomiting (41%), anorexia (44%), diarrhea (38%), general fatigue (31%), alopecia (25%), elevation of transaminase levels (19%), skin rash (9%), and fever (25%). A hypersensitivity reaction consisting of flushing, dyspnea, and hypotension occurred in one patient at dose level 2. No stomatitis or edema was observed during this trial. There was no evidence of cumulative toxicity of leukopenia, anemia, edema, and alopecia in the subsequent courses at different dose levels. There were no treatment-related deaths during this trial.
Pharmacokinetics Plasma samples for docetaxel were obtained from 26 patients during their first course of treatment (day 2). Four patients were treated with 30 mg/m2 of docetaxel, whereas 11 (six at dose level 2, five at dose level 3), nine (three at dose level 4, six at dose level 5A), and two patients received 40 mg/m2, 50 mg/m2, and 60 mg/m2, respectively. Plasma disappearance was biphasic or triphasic. The plasma concentration-time curves for the different doses of docetaxel are shown in Fig 1, and the pharmacokinetic parameters derived from the plotted data are listed in Table 5. The results obtained here are consistent with those obtained with docetaxel used as a single agent.23 There was a weak correlation between the dose of docetaxel and the plasma AUC value (r = 0.6753; r = 0.6753; 95% confidence interval, 0.39 to 0.84).
Pharmacokinetics for CPT-11 and its active metabolite, SN-38, were obtained in 25 patients on day 1 (Fig 2 and Table 6). The Cmax of CPT-11 were attained near the end of the infusion, and the plasma disappearance was biphasic. SN-38 was rapidly formed from the parent compound, and the Cmax was reached between 0 and 2 hours after the completion of the CPT-11 infusion. The plasma SN-38 concentration decreased more slowly than did that of CPT-11 (Fig 2). Because there were wide interindividual differences in the kinetics of SN-38 at each dose level, the AUC of SN-38 was poorly related to the CPT-11 dose (r = 0.0412; 95% confidence interval, -0.36 to 0.43).
Pharmacodynamics The pharmacodynamic model relating the percentage decrease in ANC to docetaxel AUC did not provide a reasonable fit (r = 0.5918; 95% confidence interval, 0.27 to 0.80). Docetaxel AUC was hardly related to a decrease in leukocytes (r = 0.1816; 95% confidence interval, -0.22 to 0.53). In addition, CPT-11 or SN-38 AUC was also unrelated to the percentage decrease in neutrophils. No relationship between the studied parameters and the response or survival could be observed.
Response and Survival
Of the 30 assessable patients, only two (7%) were still alive as of August 17, 1999. One patient was lost during the follow-up 15 weeks after the beginning of treatment. The median survival time for all 30 patients was 48 weeks (stage IIIB patients, 89 weeks; stage IV patients, 41 weeks). The 1-year actuarial survival rate in patients with stage IIIB disease was 75.0%, compared with 40.1% in the patients with stage IV disease, with an overall 1-year survival rate of 44.9%.
The systemic treatment currently recommended in patients with a good performance status is cisplatin-based combination chemotherapy. However, thanks to the availability of several newer agents with a favorable toxicity profile as well as innovative, nonoverlapping mechanisms of action,7,14,26-28 there now seems to be an increasing opportunity to develop new treatment programs for advanced NSCLC that do not include cisplatin. Although a combination of docetaxel and CPT-11 seems to be one of the promising new combination regimens, no phase I studies on this combination had previously been performed. In light of this information, we carried out this phase I study of docetaxel and CPT-11 to treat previously untreated patients with advanced NSCLC. Furthermore, the results in this study are relevant for diseases other than NSCLC against which docetaxel and CPT-11 show antitumor activity. The spectrum of toxicities for docetaxel combined with CPT-11 resembled that of each agent alone. As expected, leukopenia, neutropenic fever, and diarrhea were the principal DLTs of this combination regimen (Table 3). Leukopenia and neutropenic fever are typical toxicities of both drugs.7,29 Grade 4 neutropenia lasting more than 3 days occurred in four of 30 patients and seemed to be dose-dependent. Grade 4 neutropenia associated with fever was noted in two patients. Diarrhea, which could be attributed to CPT-11,29 was another dose-limiting adverse effect in this trial, with eight patients having grade 2 or worse diarrhea. Although significant diarrhea is uncommon with docetaxel monotherapy, with the incidence of grade 3 or 4 diarrhea being 4%,30 an increased incidence was also reported with cisplatin by Millward et al,31 in which grade 2 or worse diarrhea occurred in 13 (54%) of 24 patients, with 21% having grade 3 or 4 diarrhea. High-dose loperamide, which was reported efficacious by Abigerges et al,32 usually displayed a clear-cut value. Other DLTs were grade 3 liver dysfunction (elevation of ALT level) and infection. The incidence of toxicities attributable to docetaxel, such as hypersensitivity reaction, skin rash, and edema, was very low and was hardly a reason for treatment discontinuation, except with one patient. The DLT rates were 50% at dose level 5A and 100% at dose level 5B, which clearly precluded a further increase of the doses. On the basis of these results, we concluded that the MTD achieved in this study was the docetaxel/CPT-11 dose level of 50 mg/m2/60 mg/m2 (level 5A), or 60 mg/m2/50 mg/m2 (level 5B). The recommended dose for further phase II trials was the docetaxel/CPT-11 dose level of 50 mg/m2/50 mg/m2 (level 4). Because the recommended doses of single-agents docetaxel and CPT-11 are 60 mg/m2 and 100 mg/m2 in Japan, respectively, the recommended dose of CPT-11 in combination is substantially lower than the recommended dose of the single-agent CPT-11, whereas a clinically relevant single-agent dose (83%) of docetaxel can be administered in this combination regimen. Because neutropenia is the major DLT common to both of these agents, the use of recombinant human granulocyte colony-stimulating factor may be one way to allow higher doses of both agents to be given in combination without incurring significant myelosuppression, especially neutropenia. Another logical approach would be a phase I study exploring the MTD of CPT-11 on days 1 and 8 plus docetaxel on day 8 every 21 days, because frequent dose omissions were observed in this trial because of leukopenia and or diarrhea on day 15. Although hepatic metabolism and biliary excretion play a principal role in the metabolism and clearance of both docetaxel and CPT-11, no significant interactions on the plasma pharmacokinetics between docetaxel, CPT-11, and the CPT-11 active metabolite SN-38 were observed. This may be because of the difference in the principal mechanisms of hepatic involvement in the metabolism and disposition of docetaxel and CPT-11. Docetaxel is primarily metabolized by hepatic cytochrome P450 3A4 and 3A5 to its hydroxylation product (RPR104952). The subsequent oxidation of RPR104952 to two diastereomers (RPR111059 and RPR111026) was primarily catalyzed by cytochrome P450 3A3, with cytochrome P450 3A5 accounting for a minor degree of drug disposition.33 However, CPT-11 may not be the main metabolizing agent of this enzyme system. CPT-11 is hydrolyzed by carboxylesterase to SN-38, a compound that is at least a 200 times more potent inhibitor than CPT-11 of topoisomerase I in vitro.34-36 The activity of the enzyme is primarily found in the liver, gastrointestinal tract epithelium, and tumor tissue. Most of the resulting SN-38 is conjugated by uridine diphosphate–glucuronyl transferase and is excreted into the bile as a glucuronide-conjugate.35,37 The response rate of 37% and the median survival time of 48 weeks obtained in this study were comparable to those previously reported for trials of other combination chemotherapy regimens in patients with NSCLC.38 Furthermore, this regimen could be an alternative for patients who can not receive cisplatin-containing regimens. However, it is difficult to make valid conclusions about the ultimate clinical activity of this combination regimen on the basis of this phase I study. Therefore, phase II/III trials are needed to allow a precise estimate of the degree of activity of this regimen against advanced NSCLC. In conclusion, this study showed that 50 mg/m2 of docetaxel (day 2) plus 50 mg/m2 of CPT-11 (days 1, 8, and 15) repeated at 4-week intervals is the appropriate schedule for future phase II trials in patients with advanced NSCLC. The major DLTs were diarrhea, leukopenia, neutropenic fever, and liver dysfunction. In this phase I study of 30 patients with advanced NSCLC, we observed 11 (37%) partial responses. Although the response rate in this study seems encouraging and is within the range of results obtained with cisplatin-containing regimens, superiority should be determined by a process of randomized trials in terms of response, survival, safety, quality of life, and cost-effectiveness.
This work was supported by a grant from Rhone-Poulenc Rorer Japan, Inc, and Chugai Pharmaceutical Co, Ltd, Tokyo, Japan. We thank Toru Sasaki, Masayuki Takagishi, and Dr Masaki Kashimura for their help with data collection and the pharmacokinetic analysis. Standards of CPT-11 and SN-38 were kindly provided by Yakult Honsha Co, Ltd (Tokyo, Japan).
1. Gueritte-Voegelein F, Guenard D, Lavelle F, et al: Relationships between the structure of taxol analogues and their antimitotic activity. J Med Chem 34:992–998, 1991[Medline]
2.
Ringel I, Horwitz SB: Studies with RP 56976 (taxotere): A semisynthetic analogue of taxol. J Natl Cancer Inst 83:288–291, 1991 3. Denis JN, Greene AE, Guenard D, et al: A highly efficient practical approach to natural taxol. J Am Chem Soc 110:5917–5919, 1988
4.
Bissery MC, Guenard D, Gueritte-Voegelein F, et al: Experimental antitumor activity of taxotere (RP 56976, NSC 628503), a taxol analogue. Cancer Res 51:4845–4852, 1991 5. Harrison SD, Dykes DJ, Sheperd RV, et al: Response of human tumor xenografts to taxotere. Proc Am Assoc Cancer Res 33:526, 1992 (abstr 3144) 6. Nicoletti MI, Massazza G, Abbott BJ, et al: Taxol and taxotere antitumor activity on human ovarian carcinoma xenografts. Proc Am Assoc Cancer Res 33:519, 1992 (abstr 3101) 7. Miller VA: Docetaxel in the management of advanced non-small cell lung cancer. Semin Oncol 25:15–19, 1988 (suppl 8)
8.
Kunimoto T, Nitta K, Tanaka T, et al: Antitumor activity of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin, a novel water-soluble derivative of camptothecin, against murine tumors. Cancer Res 47:5944–5947, 1987 9. Matsuzaki T, Yokokura T, Mutai M, et al: Inhibition of spontaneous and experimental metastasis by a new derivative of camptothecin, CPT-11, in mice. Cancer Chemother Pharmacol 21:308–312, 1988[Medline] 10. Tsuruo T, Matsuzaki T, Matsushita M, et al: Antitumor effect of CPT-11, a new derivative of camptothecin, against pleiotropic drug-resistant tumors in vitro and in vivo. Cancer Chemother Pharmacol 21:71–74, 1988[Medline] 11. Tsuda H, Takatsuki K, Ohno R, et al: Treatment of adult T-cell leukemia-lymphoma with irinotecan hydrochloride (CPT-11). Br J Cancer 70:771–774, 1994[Medline] 12. Negoro S, Fukuoka M, Niitani H, et al: Phase II study of CPT-11, new camptothecin derivative, in small cell lung cancer (SCLC). Proc Am Soc Clin Oncol 10:241, 1991 (abstr 822)
13.
Masuda N, Fukuoka M, Kusunoki Y, et al: CPT-11: A new derivative of camptothecin for the treatment of refractory or relapsed small-cell lung cancer. J Clin Oncol 10:1225–1229, 1992 14. Fukuoka M, Niitani H, Suzuki A, et al: Phase II study of CPT-11, a new derivative of camptothecin, for previously untreated non–small-cell lung cancer. J Clin Oncol 10:16–20, 1992[Abstract]
15.
Shimada Y, Yoshino M, Wakui A, et al: Phase II study of CPT-11, a new camptothecin derivative, in metastatic colorectal cancer. J Clin Oncol 11:909–913, 1993 16. Takeuchi S, Takamizawa H, Takeda Y, et al: Clinical study of CPT-11, camptothecin derivative, on gynecological malignancy. Proc Am Soc Clin Oncol 10:189, 1991 (abstr 617) 17. Okishio K, Kudoh S, Hirata K, et al: Schedule dependent additive effect of docetaxel and irinotecan in vitro. Proc Jpn J Cancer Res 86:619, 1995 (abstr 2252)
18.
Tobinai K, Kohno A, Shimada Y, et al: Toxicity grading criteria of the clinical oncology group. Jpn J Clin Oncol 23:250–257, 1993
19.
Mountain CF: A new international staging system for lung cancer. Chest 89:225S–233S, 1986 (suppl 4) 20. World Health Organization: WHO Handbook for Reporting Results of Cancer Treatment. Geneva, Switzerland, World Health Organization, WHO offset publication 48, 1979 21. Sumiyoshi H, Fujiwara Y, Ohune T, et al: High-performance liquid chromatographic determination of irinotecan (CPT-11) and its active metabolite (SN-38) in human plasma. J Chromatogr B Biomed Appl 670:309–316, 1995[Medline] 22. Vergniol JC, Bruno R, Montay G, et al: Determination of Taxotere in human plasma by a semi-automated high-performance liquid chromatographic method. J Chromatogr 582:273–278, 1992[Medline]
23.
Extra J-M, Rousseau F, Bruno R, et al: Phase I and pharmacokinetic study of Taxotere (RP 56976; NSC 628503) given as a short intravenous infusion. Cancer Res 53:1037–1042, 1993 24. Yamaoka K, Tanigawara Y, Nakagawa T, et al: A pharmacokinetic analysis program (multi) for microcomputer. J Pharmacobiodyn 4:879–885, 1981[Medline] 25. Holford HN, Sheiner LB: Kinetics of pharmacologic response. Pharmacol Ther 16:143–166, 1982[Medline] 26. Depierre A, Lemarie E, Dabouis G, et al: A phase II study of Navelbine (vinorelbine) in the treatment of non–small-cell lung cancer. Am J Clin Oncol 14:115–119, 1991[Medline]
27.
Chang AY, Kim K, Glick J, et al: Phase II study of Taxol, merbarone, and piroxantrone in stage IV non-small cell lung cancer: The Eastern Cooperative Oncology Group results. J Natl Cancer Inst 85:388–394, 1993
28.
Abratt RP, Bezwada WR, Falkson G: Efficacy and safety profile of gemcitabine in non–small-cell lung cancer: A phase II study. J Clin Oncol 12:1535–1540, 1994 29. Masuda N, Kudoh S, Fukuoka M: Irinotecan (CPT-11): Pharmacology and clinical applications. Crit Rev Oncol Hematol 24:3–26, 1996[Medline] 30. Cortes JE, Pazdur R: Docetaxel. J Clin Oncol 13:2643–2655, 1995[Abstract]
31.
Millward MJ, Zalcberg J, Bishop JF, et al: Phase I trial of docetaxel and cisplatin in previously untreated patients with advanced non–small-cell lung cancer. J Clin Oncol 15:750–758, 1997
32.
Abigerges D, Armand JP, Chabot GG, et al: Irinotecan (CPT-11) high-dose escalation using intensive high-dose loperamide to control diarrhea. J Natl Cancer Inst 86:446–449, 1994 33. Shou M, Martinet M, Korzekwa KR, et al: Role of human cytochrome P450 3A4 and 3A5 in the metabolism of taxotere and its derivatives: Enzyme specificity, interindividual distribution and metabolic contribution in human liver. Pharmacogenetics 8:391–401, 1998[Medline] 34. Tsuji T, Kaneda N, Kado K, et al: CPT-11 converting enzyme from rat serum: Purification and some properties. J Pharmacobiodyn 14:341–349, 1991[Medline]
35.
Kaneda N, Nagata H, Furuta T, et al: Metabolism and pharmacokinetics of the camptothecin analogue CPT-11 in the mouse. Cancer Res 50:1715–1720, 1990
36.
Kawamoto Y, Aonuma M, Hirota Y, et al: Intracellular roles of SN-38, an active metabolite of the camptothecin derivative CPT-11, in the anti-tumor effect of CPT-11. Cancer Res 51:4187–4191, 1991
37.
Kaneda N, Yokokura T: Nonlinear pharmacokinetics of CPT-11 in rats. Cancer Res 50:1721–1725, 1990 38. Bunn PA: Triplet chemotherapy combinations with new agents: Is there a rationale? Semin Oncol 25:55–61, 1998 (suppl 9) Submitted November 2, 1999; accepted April 11, 2000.
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
) was calculated by the linear trapezoidal rule from time zero up to the last measurable data point, with extrapolation to infinity. Clearance was calculated by dividing the dose received by the AUC. The volume of distribution at steady state was calculated by the following equation: clearance x [mean residual time] x [infusion time/2]. Pharmacodynamic analysis was carried out using WINNonlin Version 2.1 (Scientific Consultant, Apex, NC). The relationship between the percentage change in the ANC and AUC or total dose was explored using a sigmoid maximum-effect model. The percent change in ANC was calculated by using the following equation: % change in ANC = ([pretreatment ANC - nadir ANC]/pretreatment ANC) x 100.
2 test or Fisher’s exact test, and P < .05 was considered to indicate statistical significance. 
), dose level 2 (x), dose level 3 (
), dose level 4 (
), dose level 5A (
), or dose level 5B (
), and the mean results for four patients (
), dose level 4 (
