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© 1999 American Society for Clinical Oncology Phase I and Pharmacokinetic Study of a Daily Times 5 Short Intravenous Infusion Schedule of 9-Aminocamptothecin in a Colloidal Dispersion Formulation in Patients With Advanced Solid TumorsFrom the Department of Medical Oncology, Antoni van Leeuwenhoek Hospital/the Netherlands Cancer Institute, Amsterdam; the Department of Pharmacy and Pharmacology, Slotervaart Hospital/the Netherlands Cancer Institute, Amsterdam, the Netherlands; and Pharmacia and Upjohn, Oncology Research and Development, Milan, Italy. Address reprint requests to V.M.M. Herben, PhD, Department of Pharmacy and Pharmacology, Slotervaart Hospital/the Netherlands Cancer Institute, Louwesweg 6, 1066 EC Amsterdam, the Netherlands.
PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of 9-aminocamptothecin (9-AC) in a colloidal dispersion (CD) formulation administered as a 30-minute intravenous (IV) infusion over 5 consecutive days every 3 weeks.
PATIENTS AND METHODS: Patients with solid tumors refractory to standard therapy were entered onto the study. The starting dose was 0.4 mg/m2/d. The MTD was assessed on the first cycle and was defined as the dose at which RESULTS: Thirty-one patients received 104+ treatment courses at seven dose levels. The DLT was hematologic. At a dose of 1.3 mg/m2/d, three of six patients experienced grade 3 thrombocytopenia. Grade 4 neutropenia that lasted less than 7 days was observed in four patients. At a dose of 1.1 mg/m2/d, four of nine patients had grade 4 neutropenia of brief duration, which was not dose limiting. Nonhematologic toxicities were relatively mild and included nausea/vomiting, diarrhea, obstipation, mucositis, fatigue, and alopecia. Maximal plasma concentrations and area under the concentration-time curve (AUC) increased linearly with dose, but interpatient variation was wide. Lactone concentrations exceeded 10 nmol/L, the threshold for activity in preclinical tumor models, at all dose levels. Sigmoidal Emax models could be fit to the relationship between AUC and the degree of hematologic toxicity. A partial response was observed in small-cell lung cancer. CONCLUSION: 9-AC CD administered as a 30-minute IV infusion daily times 5 every three weeks is safe and feasible. The recommended phase II dose is 1.1 mg/m2/d.
9-AMINO-20(S)-CAMPTOTHECIN ([9-AC], NSC 603071, FCE 28044) is derived from the plant alkaloid camptothecin and acts through specific inhibition of topoisomerase I.1,2 9-AC has demonstrated a wide spectrum of activity in animal tumor models, including both rapidly proliferating murine leukemias and slowly growing transplantable solid tumors.3,4 Although 9-AC was the first among the synthetic camptothecin derivatives selected for advanced in vivo testing and possible clinical application, the drug was only recently introduced in the clinic. This late clinical testing was mainly due to the low water solubility of 9-AC that required a lipophilic formulation, unlike other camptothecins (eg, topotecan and irinotecan). Two formulations of 9-AC are currently being investigated. The dimethylacetamide/polyethylene glycol 400 (DMA) form, which is the formulation that was initially developed by the National Cancer Institute, has been used for most of the reported phase I and II studies. 9-AC DMA is not compatible with aqueous solutions and requires glass syringes for handling. This formulation may be replaced by a lipid colloidal dispersion (CD) preparation developed by Pharmacia & Upjohn Co (Kalamazoo, MI), which enhances the water-solubility and stability and facilitates drug delivery. The search for a treatment schedule of 9-AC—and camptothecins in general—that could possibly reproduce in patients the striking results of antitumor activity observed in preclinical studies has been the major issue in the clinical development of this compound. Preclinical studies have addressed the relevance of prolonged systemic exposure to low concentrations and short intervals between treatments for significant antitumor activity. In human HT-29 colon tumor xenografts, subcutaneous injections of 9-AC suspensions established a depot with gradual release of the drug and resulted in complete regression of implanted tumors without apparent toxicity.5 Instead, solutions of 9-AC delivered at identical dosages were ineffective, producing high plasma lactone levels of shorter duration. On the basis of preclinical findings, a 72-hour continuous infusion repeated every 2 to 3 weeks was selected for initial phase I clinical testing of 9-AC DMA.6,7 Various intravenous (IV) administration schedules, using both DMA and CD formulations, are currently being evaluated, including 24-hour and more prolonged continuous infusion schedules of up to 21 days every 4 weeks.8-10 Oral administration is also being tested.11 Taking into consideration the experience with the analog topotecan12 as well as the preclinical and clinical findings with 9-AC thus far, a phase I trial was initiated to evaluate the feasibility, safety, and pharmacokinetics of 9-AC CD administered as a 30-minute IV infusion daily for 5 days every 3 weeks in patients with advanced solid tumors.
Eligibility Criteria Patients with histologic or cytologic proof of malignant solid tumor, for whom no recognized therapy was available for their stage of disease, were eligible. Other eligibility criteria included age  18 years, World Health Organization (WHO) performance status  2, and estimated life expectancy 12 weeks. Previous chemotherapy had to be discontinued for at least 4 weeks before entry onto the study, or for 6 weeks in case of mitomycin or nitrosourea. Patients were required to have acceptable bone marrow function (defined as neutrophil count 2,000/µL and platelet count 100,000/µL), adequate hepatic function (defined as serum bilirubin within normal limits of laboratory range, and aminotransferases and alkaline phosphatase 2.5 times the normal upper limit), and adequate renal function (defined as serum creatinine 1.5 mg/dL or 133 µmol/L). Ineligibility criteria included a history of treatment with other camptothecins and/or intensive ablative regimens requiring peripheral stem-cell transplantation or autologous bone marrow transplantation, known brain or leptomeningeal disease, severe systemic disease, active infection, or known allergy to soy beans. The study protocol was approved by the Medical Ethics Committee of the hospital, and all patients gave written informed consent.
Toxicity and Response Evaluation
Dose Escalation
Four dose levels were anticipated: 0.40, 0.50, 0.60, and 0.72 mg/m2/d. If no MTD was reached at this dose, then further escalations by 20% of the previous level would follow until the MTD was reached. At least three new patients were to be recruited on each dose level. Three additional patients (total of six) were treated on a dose level if one of the first three patients exhibited DLT. Upon identification of the MTD, at least three additional patients who were untreated or marginally pretreated were entered at the next lower dose level to define the MTD for this category of patients. Treatment cycles were repeated every 21 days, provided patients had sufficiently recovered from any drug-related toxicity associated with the previous course (nonhematologic toxicity
Drug Administration
Pharmacokinetics Within 3 days after sampling, methanol extracts were subjected to solid-phase extraction to separate lactone from carboxylate forms of 9-AC, as described earlier.15 Plasma levels of 9-AC as the lactone form and the total of lactone and carboxylate forms were determined on a validated reversed-phase high-performance liquid chromatography system with fluorescence detection, as developed in our laboratory.15 Urine was diluted (1:25 to 1:50) with methanol, acidified with water (pH 2.2), and a 20-µL aliquot was injected into the high-performance liquid chromatography column. The chromatographic conditions for the quantification of 9-AC as the total of lactone and carboxylate forms in urine were identical to those in plasma.
The pharmacokinetic parameters were calculated using a model-independent method. For each individual, the maximum drug concentration (Cmax) was generated directly from the experimental data. The duration of 9-AC lactone levels greater than a concentration of 10 nmol/L (t > 10 nmol/L) was determined using linear logarithmic interpolation. The terminal-rate constant, k, was determined by log-linear regression analysis of the terminal phase of the plasma concentration-time curve. The area under the concentration-time curve (AUC) and the area under the first-moment curve (AUMC) were estimated by the linear-logarithmic trapezoidal method up to the last measured data point with extrapolation to infinity using k. Total body clearance from plasma was calculated by dividing the total administered dose by the AUC. The volume of distribution at steady-state (Vdss) was determined using the following equation:
 ) was calculated as 0.693/k. Data are represented as mean ± SD.
Statistical Analysis
Pharmacokinetic-Pharmacodynamic Analysis
 is the Hill coefficient, which describes the sigmoidicity of the curve. Statistical analysis was performed with NCSS (Number Cruncher Statistical System, NCSS Statistical Software, Kaysville, UT).
Thirty-one patients received 104+ courses at seven dose levels. Patient characteristics are listed in Table 1. The planned dose escalation scheme was reconsidered in the course of the study. The following dose levels were evaluated: 0.4, 0.5, 0.6, 0.72, 0.9, 1.1, and 1.3 mg/m2/d for 5 days. The median number of courses administered per patient was three (range, one to eight). Thirty patients were assessable for toxicity during the first treatment course. One patient was not assessable because of early infusion termination on the third day of the first course. She experienced severe abdominal pain that was not drug-related. X-ray, ultrasound, and endoscopy showed no abnormalities, and the patient was treated with pain medication. After recovery, the patient received a second course, but the infusion was stopped on the third day because of disorientation and drowsiness. She died 1 week later. Three patients did not receive a second course according to this protocol, because of rapid progressive disease (two patients) and severe hematologic toxicity resulting in rapid clinical deterioration (one patient entered at a dose of 1.3 mg/m2/d).
Hematologic Toxicity
Of 29 assessable courses administered at the recommended phase II dose of 1.1 mg/m2/d, six courses (21%) were delayed for 1 week because of unresolved neutropenia on day 21, and one course was postponed because of a patient's request. One patient treated at 1.1 mg/m2/d and two patients treated at 1.3 mg/m2/d needed dose reductions to the next lower dose level after the first treatment cycle because of neutropenia; in one patient the dose was further reduced to 0.9 mg/m2/d after the third course because of hematologic toxicity. Episodes of febrile neutropenia were observed in one patient treated at 0.9 mg/m2/d and two patients treated at the 1.3 mg/m2/d dose level. There was no definite indication of cumulative myelosuppression on repeated dosing, evidenced by similar or less prominent neutrophil, hemoglobin, and platelet nadirs in later courses compared with the first course (Table 3). Although there was a trend toward increased anemia in the few patients treated with multiple courses of the 0.4 and 0.5 mg/m2/d doses, no cumulative effect was noted at the two highest dose levels, at which larger numbers of patients and treatment courses were available for analysis. The neutrophil nadir typically occurred between days 7 and 14. The duration of grade 4 neutropenia was usually short, with recovery to grade 3 within 3 days (range, 1 to 6 days). Thrombocytopenia was rare. Severe (grade 3) thrombocytopenia was not observed until a dose of 1.3 mg/m2/d (Table 2). Three patients treated on this dose level experienced grade 3 thrombocytopenia (21%). Anemia occurred regularly (grade 1/2 in 82% of courses), but was severe (grade 3) in only one course at a dose of 1.1 mg/m2/d. A total of 13 units of packed RBCs were required during six courses involving three patients entered at a dose of 1.1 mg/m2/d and three patients entered at a dose of 1.3 mg/ m2/d.
Nonhematologic Toxicity
Pharmacokinetics
The influence of prior exposure to 9-AC on the AUC could be examined in 21 patients who had pharmacokinetic studies performed on day 5 of the first course, and during 18 second courses, five third courses, and three fourth courses, using a limited sampling strategy. Overall, the lactone or total AUC were not significantly different after 5 consecutive days of administration (Fig 1) or during subsequent courses compared with the first course (data not shown), indicating that no drug accumulation occurred. Baseline patient and biochemical characteristics were examined as possible determinants of the pharmacokinetic parameters. No significant relationships could be identified between total body clearance of 9-AC lactone or total drug, or the lactone-to-total ratio and the following characteristics: age, gender, weight, height, performance status, serum creatinine, transaminases, serum bilirubin, albumin and alkaline phosphatase, prior abdominopelvic irradiation, and liver metastases.
Pharmacodynamics
Responses
The presented phase I trial indicates that 9-AC in its novel CD formulation administered as a 30-minute IV infusion daily for 5 days every 3 weeks is feasible and safe. Hematologic toxicity was dose-limiting, which is similar to that seen with other infusion schedules of 9-AC.6,7 At a daily dose of 1.3 mg/m2/d, three of six patients experienced grade 3 thrombocytopenia, which, according to the predefined criteria for the MTD, precluded further dose escalation. These results suggest that myeloid growth factor support is unlikely to permit further dose escalation. Grade 4 neutropenia was observed in four patients entered at this dose level, but was not dose limiting. The recommended dose for further phase II testing is 1.1 mg/m2/d (5.5 mg/m2) every 3 weeks for both heavily and minimally pretreated patients. Six of the nine patients at this dose level were minimally pretreated, with only one prior chemotherapeutic regimen and no extensive radiotherapy. Nonetheless, neutropenia was equally frequent in both groups, for which reason the recommended dose is similar for both patient populations. Nonhematologic toxicities attributed to 9-AC treatment included nausea and vomiting, diarrhea, mucositis, fatigue, and alopecia. Substantial interpatient variability in pharmacokinetics of 9-AC was observed. Because patients' physiopathologic characteristics such as age, serum bilirubin, and albumin were recently reported to influence the pharmacokinetics of 9-AC,17 we examined several factors that could play a role in 9-AC disposition. No obvious influence was noted for patient characteristics and liver or renal function; however, the limited number of patients may obscure such relationships. Intrapatient variability was small, indicating that repeated or prior exposure to 9-AC does not markedly alter the drug's kinetic profile. Preliminary data suggested differences in pharmacology between the CD formulation of 9-AC used in the present study and the DMA formulation used in initial clinical trials.18 After a 72-hour infusion of 9-AC CD, total drug plasma concentrations were similar to those obtained with the same dose of 9-AC DMA. However, lactone concentrations were more than two-fold higher than levels achieved with the DMA formulation. 9-AC lactone may be stabilized by the CD vehicle, resulting in higher plasma levels and longer terminal half-life. A comparison of pharmacokinetic parameters obtained in our study with previously published data showed that 9-AC lactone clearance (15.7 ± 9.2 L/h/m2) and volume of distribution at steady-state (89 ± 69 L/m2) were similar to those obtained after 24-hour infusion of the CD formulation (median, 18.0 L/h/m2 and 111 L/m2, respectively),8 whereas after 72-hour infusion of 9-AC DMA, significantly higher values were reported (24.5 ± 7.3 L/h/m2, P < .0001, and 195 ± 114 L/m2, P = .006, respectively).19 However, these differences may also be explained by differences in dosage and administration schedule and the wide interpatient variation rather than formulation of the drug. In contrast to results obtained with a 72-hour infusion schedule,19 the present study showed no evidence of nonlinear pharmacokinetics over the dose range studied. Clearance and lactone-to-total AUC ratio were independent of the dose.
Preclinical studies have demonstrated evident schedule-dependent cytotoxicity for 9-AC. In the advanced stage subcutaneous human HT-29 colon tumor xenograft model, a solution of 9-AC delivered subcutaneously induced only marginal activity. Instead, at comparable dose-intensity (DI), a 9-AC suspension caused regression of the growing tumor, which was not a function of total dose as much as a function of exposure and plasma concentrations. Pharmacokinetic analysis showed that subcutaneous treatment with 9-AC suspensions simulated, to some extent, infusion schedules. Complete tumor regression was observed in xenografts, provided lactone concentrations of approximately 10 nmol/L were achieved repeatedly for approximately 48 hours, with short periods of recovery between courses.5 The presented daily x 5 bolus schedule was able to achieve 9-AC lactone levels exceeding this threshold of In agreement with the preclinical data obtained in xenografts, the clinical experience with the analog topotecan suggest that toxicity and antitumor activity are dependent on modality and frequency of the administration schedule rather than DI. When topotecan was administered in the approved daily x 5 bolus schedule every 3 weeks,21-23 higher DI could be delivered compared with a 5-day continuous infusion every 3 weeks.24 Both schedules showed objective antitumor activity, but the 5-day continuous infusion schedule seemed to be more myelosuppressive. By shortening the exposure to the drug to 24 hours, higher DI could be delivered,25,26 but no antitumor activity was observed in recurrent ovarian cancer.27 By prolonging the exposure to 21-day continuous infusion every 4 weeks, the initial DI was high,28 but because of cumulative myelosuppression, the DI had to be decreased with repeated administration.29 The optimal administration schedule of 9-AC in the clinic has not yet been defined. The recommended dose of the presented daily x 5 schedule (DI, 1.8 mg/m2/wk) is higher than with 24-hour infusion of 9-AC weekly for 4 weeks every 5 weeks8 or 72-hour infusion schedules every 2(DI, 1.3 mg/m2/wk) or 3 weeks (1.1 mg/m2/wk).6,7 Subsequent phase II studies of the 72-hour infusion schedule failed to show substantial antitumor activity in colorectal cancer, but severe toxicities were encountered that necessitated treatment delays and dose reductions in the majority of patients.30,31 Preliminary results of other schedules showed that prolonged 120-hour (DI, 1.8 mg/m2/wk)20 and 21-day continuous infusions (DI, 2.1 and 3.15 mg/m2/wk for the DMA and CD formulations, respectively)9 were more dose intense than the 72-hour infusion schedule and showed preliminary evidence of antitumor activity. Given the relatively high DI and the preliminary evidence of activity, the presented daily x 5 IV bolus schedule is a promising way of delivering 9-AC. Phase II trials will be needed to assess whether the use of this intermittent dosing schedule translates into improved therapeutic efficacy.
1. Hsiang Y-H, Hertzberg R, Hecht S, et al: Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J Biol Chem 260:14873-14875, 1985
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Dahut W, Harold N, Takimoto C, et al: Phase I and pharmacologic study of 9-aminocamptothecin given by 72-hour infusion in adult cancer patients. J Clin Oncol 14:1236-1244, 1996 8. Siu LL, Oza AM, Eisenhauer EA, et al: Phase I and pharmacologic study of 9-aminocamptothecin colloidal dispersion formulation given as a 24-hour continuous infusion weekly times four every 5 weeks. J Clin Oncol 16:1122-1130, 1998[Abstract] 9. Hochster H, Liebes L, Speyer J, et al: Phase I and pharmacodynamic study of prolonged infusion 9-amino-camptothecin in two formulations. Proc Am Soc Clin Oncol 16:201a, 1997 (abstr) 10. Tran HT, Madden T, Newman RA, et al. Phase I pharmacokinetic trial of 9-aminocamptothecin given as a 15 minute infusion daily x 5 for 2 to 4 weeks. Proc Am Assoc Cancer Res 39:522, 1998 (abstr) 11. De Jonge MJA, Punt CJA, Sparreboom A, et al: Phase I and pharmacologic study on oral (PEG 1000) 9-amino-camptothecin in patients with advanced solid tumors. Ann Oncol 9:64, 1998 (abstr) 12. Creemers GJ, Lund B, Verweij J: Topoisomerase I inhibitors: Topotecan and irenotecan. Cancer Treat Rev 20:73-96, 1994[Medline] 13. National Cancer Institute: Guidelines for Reporting of Adverse Drug Reactions. Bethesda, MD, Division of Cancer Treatment, National Cancer Institute, 1988 14. World Health Organization: WHO Handbook for Reporting Results of Cancer Treatment. Geneva, Switzerland, World Health Organization, 1979 15. Van Gijn R, Herben VMM, Hillebrand MJX, et al: High-performance liquid chromatography analysis of 9-aminocamptothecin, as the lactone form and as the total of the lactone and the hydroxycarboxylate forms, in micro volumes of human plasma. J Pharm Biomed Anal 17:1257-1265, 1998[Medline] 16. Holford NHG, Sheiner LB: Kinetics of pharmacologic response. Pharmacol Ther 16:143-166, 1992 17. Minami H, Mick R, Vokes EE, et al: Pharmacodynamic models for leukopenia and thrombocytopenia of 9-aminocamptothecin. Proc Am Soc Clin Oncol 15:179, 1996 (abstr) 18. Liang MD, Dahut W, Quinn MF, et al: Preclinical and clinical studies of a new colloidal dispersion formulation of 9-aminocamptothecin. Proc Am Assoc Cancer Res 37:432, 1996 (abstr) 19. Takimoto CH, Dahut W, Marino MT, et al: Pharmacodynamics and pharmacokinetics of a 72-hour infusion of 9-aminocamptothecin in adult cancer patients. J Clin Oncol 15:1492-1501, 1997[Abstract] 20. Takimoto CH, Dahut W, Harold N, et al: A phase I trial of a prolonged infusion of 9-aminocamptothecin in adult patients with solid tumors. Proc Am Soc Clin Oncol 15:488, 1996 (abstr)
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Blaney SM, Balis FM, Cole DE, et al: Pediatric phase I trial and pharmacokinetic study of topotecan administered as a 24-hour continuous infusion. Cancer Res 53:1032-1036, 1993 27. Hoskins P, Eisenhauer E, Beare S, et al: Randomized phase II study of two schedules of topotecan in previously treated patients with ovarian cancer: A National Cancer Institute of Canada Clinical Trials Group Study. J Clin Oncol 16:2233-2237, 1998[Abstract] 28. Hochster H, Liebes L, Speyer J, et al: Phase I trial of low-dose continuous topotecan infusion in patients with cancer: An active and well-tolerated regimen. J Clin Oncol 12:553-559, 1994[Abstract] 29. Creemers GJ, Gerrits CJH, Schellens JHM, et al: Phase II and pharmacologic study of topotecan administered as a 21-day continuous infusion to patients with colorectal cancer. J Clin Oncol 14:2540-2545, 1996[Abstract] 30. Pazdur R, Diaz-Canton E, Ballard WP, et al: Phase II trial of 9-aminocamptothecin administered as a 72-hour continuous infusion in metastatic colorectal carcinoma. J Clin Oncol 15:2905-2909, 1997[Abstract] 31. Saltz LB, Kemeny NE, Tong W, et al: 9-Aminocamptothecin by 72-hour continuous intravenous infusion is inactive in the treatment of patients with 5-fluorouracil-refractory colorectal carcinoma. Cancer 80:1727-1732, 1997[Medline] Submitted August 24, 1998; accepted January 27, 1999. This article has been cited by other articles:
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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TOP
ABSTRACT
INTRODUCTION
, •) and carboxylate forms of 9-AC (
, 
) in eight patients receiving 1.1 mg/m2/d as a 30-minute IV infusion on day 1 (——) and day 5 (- - -) of the first course. Error bars were omitted for legibility.
