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© 2000 American Society for Clinical Oncology Phase I and Pharmacokinetic Study of a New Taxoid, RPR 109881A, Given as a 1-Hour Intravenous Infusion in Patients With Advanced Solid TumorsFrom the Division of Internal Medicine, National Cancer Center Hospital, Tokyo; Department of Internal Medicine and Department of Surgery, National Shikoku Cancer Center Hospital, Matsuyama City; Department of Obstetrics and Gynecology, Kawasaki Medical School, Kurashiki City; Department of Internal Medicine, National Kyushu Cancer Center, Fukuoka City; and Rhône-Poulenc Rorer Japan, Inc, Ibaraki Laboratory, Research and Development Division, Chiyoda-Machi, Ibaraki Prefecture, Ibaraki, Japan. Address reprint requests to Takayasu Kurata, MD, or Yashuhiro Shimada, MD, Division of Internal Medicine, National Cancer Center Hospital, 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045; email welnet{at}urban.ne.jp
PURPOSE: RPR 109881A is a new semisynthetic taxoid compound that has a similar mechanism of action to docetaxel. The purpose of this phase I study was to characterize the maximum-tolerated dose (MTD), toxicity profile, pharmacokinetic profile, and antitumor effects of this agent. PATIENTS AND METHODS: Nineteen eligible patients with advanced solid tumors were enrolled. RPR 109881A was administered as a 1-hour intravenous infusion every 3 weeks at doses ranging from 15 to 75 mg/m2. Pharmacokinetic evaluation was performed at the first cycle. RESULTS: Neutropenia (febrile neutropenia) and fatigue were dose-limiting toxicities at doses of 60 and 75 mg/m2 and seemed to be dose-related. Both thrombocytopenia and anemia were infrequent. Nonhematologic toxicities were generally mild. Pharmacokinetic studies indicated that RPR 109881A plasma disposition was bi- or triphasic, with a high total plasma clearance, a large volume of distribution, and a long terminal half-life. The area under the concentration-time curve (AUC) and the peak concentration of RPR 109881A seemed to increase with increasing dose proportionally, suggesting linear pharmacokinetics. Urinary excretion over 48 hours was low, with a mean of 0.8 ± 0.36% of the administered dose. A significant relationship existed between the percentage decrease of neutrophil counts and the AUC of RPR 109881A. Among 18 assessable patients, two partial and two minor responses were documented. CONCLUSION: RPR 109881A was found to be a well-tolerated and promising taxoid agent. The MTD was 75 mg/m2, and the recommended dose for phase II study was 60 mg/m2 as a 1-hour infusion every 3 weeks.
CANCER IS STILL the leading cause of death throughout the world. Although chemotherapy plays the key role for treating advanced cancer, results of currently available chemotherapy regimens are still disappointing. Recently, several new compounds, such as taxanes and camptothecins, have demonstrated promising activities. Among these compounds, the taxanes, paclitaxel and docetaxel, have the same mechanism of action and have broad antitumor activity. These compounds interact with polymerized tubulin to promote the formation of microtubules, to prevent their disassembly, and, thus, to block cell division at the G2-M phase.1-3 RPR 109881A is a novel semisynthetic taxoid compound that is prepared from 10-deacetyl baccatin III extracted from the needles of yew trees. RPR 109881A is an antimitotic agent that has a mechanism of action similar to that of docetaxel. In vitro studies against murine P388 leukemia cells showed that RPR 109881A was found to be more active than docetaxel. In vivo studies showed schedule dependency with regard to drug activity, and thus the intermittent schedule was chosen for in vivo studies to evaluate its antitumor activities. RPR 109881A had a broad spectrum of activity against the docetaxel-sensitive murine cell lines, B16 melanoma, C38 colon adenocarcinoma, 13/C breast adenocarcinoma, P03 pancreatic ductal adenocarcinoma, and, interestingly, the docetaxel-resistant P388 leukemia. Additionally, RPR 109881A shows activity against the human breast cancer cell line Calc18 and human colon cancer cell line HCT-8. Resistance to chemotherapy agents is a major obstacle to the successful treatment of malignancies. For paclitaxel and docetaxel, the 170-kd P-glycoprotein (Pgp) that functions as a drug efflux pump, encoded by the multidrug resistance-1 gene, is one of the mechanisms conferring resistance.4-7 Because preclinical data show that RPR 109881A is only minimally recognized by the Pgp, it is expected that this agent will be active against some tumors that are known to express high levels of the multidrug resistance-1 gene and Pgp (eg, colon cancer, renal cancer, and pancreatic cancer) and, moreover, against some docetaxel-resistant tumors. In addition, this compound was found to penetrate the blood-brain barrier which may also be a consequence of its decreased recognition by the Pgp. On the basis of this preclinical evidence, we undertook a phase I study in which the drug was administered as a 1-hour intravenous (IV) infusion every 3 weeks. This schedule of administration was chosen because a similar schedule has been used with docetaxel and because the 1-hour infusion would be well tolerated on an outpatient basis. The objectives of this study were as follows: (1) to determine the maximum-tolerated dose (MTD) of RPR 109881A on this particular dosing schedule and recommend the dose for further phase II studies, (2) to describe the toxicities of this agent, (3) to characterize the pharmacokinetic profile of the drug, and (4) to observe any antitumor effects.
Eligibility Patients with histologically or cytologically proven solid tumors that were refractory to standard therapy or for which there was no effective therapy were eligible. It was preferable that patients had measurable or assessable lesions. Eligibility criteria included the following: age of 20 to 74 years, Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, life expectancy of greater than 3 months, adequate organ function (WBC count  4,000/µL, neutrophil count 2,000/µL, platelet count 100,000/µL, total bilirubin level  1.5 mg/dL, AST and ALT levels 2.5 times upper normal limits, serum creatinine 1.5 mg/dL, creatinine clearance 60 mL/min), normal coagulation tests, and a normal ECG. At least 4 weeks (6 weeks in the case of nitrosourea, mitomycin, and radiation therapy against more than 20% of all the bones in the body) must have elapsed since the completion of previous therapy. Also, patients must have recovered from the toxic effects of the previous therapy. Exclusion criteria included heart failure, infection with fever, uncontrollable diabetes mellitus, obstruction or paralysis of the bowel, peripheral neuropathy, massive pleural effusion or ascites, peripheral edema, severe mental disease, active concurrent malignancies, hepatitis B or C virus infection, human immunodeficiency virus or T-cell lymphotropic virus type I infection, brain metastases, pregnancy, lactation, and the use of corticosteroids (except in patients who were taking corticosteroids less than 20 mg/d for more than 6 months). Patients who had prior paclitaxel- or docetaxel-containing chemotherapy or who had intensive chemotherapy or radiation therapy with autologous bone marrow transplantation were excluded. Patients who had a history of hypersensitivity to any drugs were also ineligible. This study was performed at National Cancer Center Hospital, National Shikoku Cancer Center Hospital, National Kyushu Cancer Center, and Kawasaki Medical School and was approved by the institutional review boards of each institution. Written informed consent was obtained from all patients. This study was conducted in accordance with Japanese Good Clinical Practice guidelines.
Pretreatment and Follow-Up Studies
Drug Administration and Dose Escalation Patients with obvious evidence of PD were withdrawn from the study. For patients receiving more than one course of treatment, subsequent courses were started after complete recovery from the toxic effects of the previous course. If more than 6 weeks passed from the previous course before recovery from toxicities, then the patient was withdrawn from study. Prophylactic use of antiemetics and hematopoietic growth factors were not allowed. If patients experienced grade 3 nausea and grade 3 vomiting or more, then administration of granisetron (3 mg/d) was allowed. Administration of granulocyte-colony stimulating factor, loperamide (2 mg/d), and spironolactone (50 mg/d) were also allowed if DLT for neutropenia, diarrhea, and edema occurred during the initial course, respectively. No premedication was used to avoid hypersensitivity reactions. However, when moderate or severe reactions occurred, 10 mg of dexachlorpheniramine or 50 mg of diphenhydramine and 20 mg of dexamethasone were planned to be administered IV, as well as before subsequent courses of RPR 109881A administration.
Pharmacokinetics RPR 109881A concentrations in plasma and urine were determined by a reverse-phase high-performance liquid chromatography with ultraviolet detection.9 This method involves a solid-phase extraction (ISOLUTECN; International Sorbent Technology, Mid Glamorgan, United Kingdom). An ultraviolet detector adjusted at 200 nm assayed RPR 109881A and RP 70617, which served as the internal standard, with peak areas being used for quantification. The lower limit of the assay was 5.0 µg/L and the linearity was confirmed up to 5,000 µg/L (weight, 1/x2) in plasma. The lower limit of assay was 20 µg/L and the linearity was confirmed up to 5,000 µg/L (weight, 1/x2) in urine.
Pharmacokinetic parameters were calculated using WinNonlin software (Scientific Consulting Inc, Cary, NC). The calculation of kinetic parameters was performed using a two- or three-compartment open model. To assess the pharmacokinetic/pharmacodynamic relationships of RPR 109881A, the percentage of decrease in absolute neutrophil or leukocyte count was calculated according to the following formula:
 ).
Between July 1996 and July 1997, 19 patients were enrolled onto this study. The patient characteristics are listed in Table 1. There were 14 male and five female patients. Most of the patients had good performance status (18 patients had performance status of 0/1, and one patient had performance status of 2) and the median age was 54 years (range, 38 to 71 years). The predominant types of tumor were lung, head and neck, colorectal, and breast. Only two of the 19 patients had received no prior therapy. Of the 17 previously treated patients, 15 had received prior chemotherapy, 14 had received surgery, and seven had received radiotherapy.
The tested doses, the number of patients, and the courses entered at each dose are listed in Table 2. The total and the median number of courses were 57 and two (range, one to seven courses), respectively. Although one patient at the dose of 45 mg/m2 received the incorrect dosage (40 mg/m2) at the first course, all patients were included in the toxicity evaluation.
The major toxicities after the first course and all courses are listed in Tables 3 and 4. With respect to hematologic toxicities, neutropenia occurred most frequently and seemed to be dose-related. Specifically, grade 4 neutropenia occurred at doses of 60 and 75 mg/m2. The median neutrophil nadir counts after the first course at each dose are listed in Table 5. The median neutrophil nadir occurred on day 9 (range, 2 to 21 days) and recovered on day 16 (range, 13 to 24 days) during the first course. Although most patients could be treated every 21 days, four patients (one at the 45 mg/m2 dose level, one at the 60 mg/m2 dose level, and two at the 75 mg/m2 dose level) experienced treatment delay because of persisting neutropenia (three patients) or liver dysfunction at day 21 (one patient). Moreover, five patients (two at the 60 mg/m2 and three at the 75 mg/m2 dose levels) required dose reduction on subsequent courses because of grade 4 neutropenia that lasted for more than 3 days. One of the two patients treated at the dose level of 60 mg/m2 who developed grade 4 neutropenia associated with fever died of infection at day 12 with grade 4 thrombocytopenia, grade 4 diarrhea, grade 4 fatigue, grade 4 dyspnea, grade 4 hyperbilirubinemia, and grade 3 elevation of AST. She was heavily pretreated for breast cancer with bone and liver metastases. Her last previous combination chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil (5-FU) was performed 4 weeks before RPR 109881A infusion. Her performance status was 2.
Nonhematologic toxicities were mild (Tables 3 and 4). Three patients (two at the 60 mg/m2 and one at the 75 mg/m2 dose levels) had grade 3 nausea during the first course. Except for the case of treatment-related death, only one patient at the dose of 75 mg/m2 developed dose-limiting fatigue during the first course, and two patients at the dose of 60 mg/m2 had grade 3 elevation of ALT during their second courses. Diarrhea was mild or moderate. Grade 1 or 2 nonspecific fever without obvious infection was observed in 12 courses. At the dose levels of 60 mg/m2 and 75 mg/m2, grade 2 skin toxicities were seen in three of 21 courses. Neurosensory toxicities were also mild, as nothing more than grade 2 toxicity was observed during all courses. No patients experienced hypersensitivity reactions or severe fluid retention.
MTD
Pharmacokinetics and Pharmacodynamics
Responses Eighteen of 19 patients were assessable for response. Two objective responses were seen. The first response was seen in a 54-year-old male patient with head and neck cancer who was previously treated with surgery and chemotherapy, which consisted of three cycles of 5-FU and cisplatin. He had a PR in right hilar lymph nodes after two courses of RPR 109881A at the dose of 45 mg/m2. He received a total of four cycles, and the response duration was 32 days. The second response was seen in a 46-year-old male patient with previously untreated non–small-cell lung cancer. A PR was noted in his disseminated pleural lesions after two courses of RPR 109881A at the dose of 60 mg/m2. He received a total of five cycles, and the response duration was 4.2 months. Moreover, two minor responses were documented. One occurred in a 58-year-old female patient with colorectal cancer who was previously treated with surgery and chemotherapy using 5-FU and cisplatin at the dose of 45 mg/m2. The other occurred in a 55-year-old male patient with previously untreated non–small-cell lung cancer at the dose of 60 mg/m2.
Taxanes, such as paclitaxel and docetaxel, have recently demonstrated promising activity against several tumor types. RPR 109881A is a novel semisynthetic taxoid compound and an antimitotic agent that has a mechanism similar to that of docetaxel. The MTD of RPR 109881A was found to be 75 mg/m2 as a 1-hour infusion in this trial. The recommended dose for phase II studies is 60 mg/m2 as a 1-hour infusion every 3 weeks. The DLTs of RPR 109881A were neutropenia and fatigue. Neutropenia was more common and dose-related. Grade 4 neutropenia was observed at doses greater than 60 mg/m2, and the nadir counts were progressively reduced with increasing dose levels. The median nadir and the median recovery values were observed on day 9 and on day 16, respectively. Only three patients experienced treatment delay because of persisting neutropenia. These results suggest that a 3-week-interval schedule is feasible. Both thrombocytopenia and anemia were infrequent in this study. Nonhematologic toxicities were generally mild. Only two patients developed grade 3 or 4 fatigue considered as a DLT. Nausea and vomiting were tolerable without prophylactic antiemetics; only three patients experienced grade 3 nausea and vomiting. Unlike paclitaxel, neurologic toxicities were mild, as more than grade 2 toxicities were not observed during all courses. Moreover, no patients experienced hypersensitivity reactions in this study. Unlike docetaxel,10-12 severe fluid retention was not observed in this study. These results suggest that RPR109881A could be less neurotoxic than paclitaxel and less allergenic than docetaxel, but this assumption should be proven in larger studies. Although one patient with previously extensively treated breast cancer who received RPR 109881A at the dose of 60 mg/m2 died of infection on day 12 with grade 4 neutropenia, DLT was observed in two of six patients. The patient who died was heavily pretreated, and she may not have sufficiently recovered from her previous chemotherapy. One other patient experienced febrile neutropenia, but fever lasted only 2 days and was not accompanied by severe infection. As described in Table 3, neutropenia in four other patients at the 60 mg/m2 dose level was grade 2 in three patients and grade 3 for one patient. From these results, neutropenia at this dose level seemed manageable, except in patients with poor bone marrow function. Therefore, 60 mg/m2 was considered feasible and is the recommended dose for phase II study. The pharmacokinetic profile of the drug RPR 109881A is characterized by a marked, interpatient-variable triphasic pattern, which is also similar to that of docetaxel. The interpatient variability may be related to differences in drug clearance. Compared with the report of the phase I study of docetaxel,10 RPR 109881A exhibited a higher total plasma clearance than docetaxel, as listed in Table 6. Moreover, a larger volume of distribution and a longer terminal half-life were observed. Hepatic metabolism with subsequent biliary excretion was considered as the main pathway of clearance for paclitaxel and docetaxel.13 For paclitaxel, the hepatic cytochrome P-450 (CYP), CYP 2C8, is responsible for the major metabolite in humans,14 whereas CYP 3A4 and CYP 3A5 are responsible for the major metabolite of docetaxel.15 Because no metabolites were detected in the conditions of the assay in the case of RPR 109881A, further research is necessary to detect the metabolic pathways. Pharmacodynamic analysis using a sigmoidal Emax model demonstrated that neutropenia and leukopenia were related to the RPR 109881A AUC. This linear pharmacokinetic pattern and pharmacodynamic analysis recommend the use of population pharmacokinetic modeling to individualize the dose setting to achieve the target AUC. Other authors have described different dosing schedules for RPR 109881A, administered as a 3-, 6-, or 24-hour infusion and as a 1-hour infusion on days 1 and 8 every 3 weeks.16-18 Irrespective of administration schedules, neutropenia was reported to be the most common DLT. A comparison of the five different administration schedules (1-, 3-, 6-, and 24-hour infusions on day 1 and 1-hour infusions on days 1 and 8) has suggested that the pharmacokinetics of RPR 109881A are not influenced by the administration schedules or the doses tested so far.19 Given these findings, the schedule as a 1-hour infusion seems to be appropriate and was chosen because it was well tolerated on an outpatient basis. In this phase I study, objective responses (PRs) were observed in two of 18 patients, and minor responses were observed in two patients. In summary, this study indicates that RPR 109881A could be a well-tolerated and promising active taxoid agent. The recommended dose for further studies is 60 mg/m2 as a 1-hour infusion every 3 weeks. The main DLTs are neutropenia or febrile neutropenia.
Supported by Rhône-Poulenc Rorer Japan, Inc, Tokyo, Japan. We thank Tetsuo Taguchi, Hisanobu Niitani, Shoji Kudo, Isao Nakao, and Yasuo Ohashi for their suggestions regarding the monitoring committee in evaluating the safety and effectiveness of the study, and Yasutsuna Sasaki for the pharmacokinetic analyses.
1. Schiff PB, Fant J, Horwitz SB: Promotion of microtubule assembly in vitro by Taxol. Nature 277: 665-667, 1979[Medline] 2. 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]
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Rowinsky EK, Donehower RC, Jones RJ, et al: Microtuble changes and cytotoxicity in leukemic cell lines treated with taxol. Cancer Res 48: 4093-4100, 1988 4. Horwitz SB, Cohen D, Rao S, et al: Taxol: Mechanisms of action and resistance. J Natl Cancer Inst Monogr 15: 55-61, 1993 5. Ford JM, Hait WN: Pharmacology of drugs that alter multidrug resistance in cancer. Pharmacol Rev 42: 155-199, 1990[Medline]
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Ringel I, Horwitz SB: Studies with RP 56976 (Taxotere): A semisynthetic analog of Taxol. J Natl Cancer Inst 83: 288-291, 1991 7. Wils P, Phung-Ba V, Warnery A, et al: Polarized transport of docetaxel and vinblastine mediated by P-glycoprotein in human intestinal epithelial cell monolayers. Biochem Pharmacol 48: 1528-1530, 1994[Medline] 8. National Cancer Institute: Guidelines for Reporting of Adverse Drug Reactions. Bethesda, MD, Division of Cancer Treatment, National Cancer Institute, 1988 9. Vergniol JC, Pasquier O: Determination of RPR 109881A in human plasma, urine and whole blood by high performance liquid chromatography: Rhône-Poulenc Rorer internal report. Paris, France, Rhône-Poulenc Rorer, 1996
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Extra JM, 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
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Burris H, Irvin R, Kuhn J, et al: Phase I clinical trial of taxotere administered as either a 2-hour or 6-hour intravenous infusion. J Clin Oncol 11: 950-958, 1993 12. Tomiak E, Piccart MJ, Kerger J, et al: Phase I study of docetaxel administered as a 1-hour intravenous infusion on a weekly basis. J Clin Oncol 12: 1458-1467, 1994[Abstract] 13. Dorr RT: Pharmacology of the taxanes. Pharmacotherapy 17: 96S–104S, 1997[Medline]
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Rahman A, Korzekwa KR, Grogan J, et al: Selective biotransformation of Taxol to 6-alpha-hydroxytaxol by human cytochrome P450 2C8. Cancer Res 54: 5543-5546, 1994 15. 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] 16. Barthier S, Dieras V, Kalla S, et al: A phase I and pharmacokinetics (PK) study of RPR 109881A given as 6-hour IV infusion in patients (pts) with advanced solid tumors. Proc Am Soc Clin Oncol 17: 194a, 1998 (abstr 747) 17. Slaughter M, Pazdur PM, Hoff C, et al: Phase I trial of RPR 109881A (RPR), a novel taxoid derivative, administered as a 24-hour continuous infusion. Proc Am Soc Clin Oncol 17: 194a, 1998 (abstr 748) 18. Eisenhauer E, Latreille J, Gelmon K, et al: Phase I trial of the new taxoid RPR 109881A in a day 1 and 8 intravenous (IV) schedule every 3 weeks: An NCI Canada clinical trials group study. Proc Am Soc Clin Oncol 17: 194a, 1998 (abstr 746) 19. Vernillet L, Semiond D, Vergniol JC, et al: Pharmacokinetics of a new taxoid (RPR 109881A): Comparison of five different administration schedules. Proc Am Soc Clin Oncol 17: 194a, 1998 (abstr 749) Submitted October 29, 1999; accepted May 1, 2000. This article has been cited by other articles:
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
