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[CANCER RESEARCH 47, 2486-2493, May 1, 1987]
Phase I Clinical and Pharmacokinetic Study of Taxol1 Peter H. Wiernik,2 Edward L. Schwartz, Janice J. Strauman, Janice P. Dutcher, Richard B. Lipton, and Elisabeth Paietta Alben Einslein Cancer Center, Monte fiore Medicai Center, Bronx, New York 10467
ABSTRACT Taxol, selected for clinical trial because of its animal antitumor activity and unique structure and mechanism of action, was administered in Cremophor by i.v. infusion over 6 h in a phase I study. Eastern Cooper ative Oncology Group toxicity grading was used. Eighty-three taxol courses were administered to 34 patients. Grade 3-4 hypersensitivity reactions occurred in 4 of 13 courses at the first 2 dose levels, but premedication with dexamethasone, diphenhydramine, and cimetidine resulted in only 3 additional Grade 1 reactions in the next 70 courses. Neurotoxicity, which resolved or improved after stopping therapy, was Grade 1 with 2 of 10 courses of 230 mg/m2 and Grades 1-3 after 11 of 12 courses of 275 mg/m2. Leukopenia, first seen (Grade 1) after 1 of 8 75 mg/m2 courses, was Grades 3-4 after 10 of 34 courses of 175-230 mg/m2 and 10 of 12 courses of 275 mg/m2. The WBC nadir occurred at a median of 10 days and the median time required for normalization of the WBC was 18 days. Alopecia began 2-3 weeks posttaxol in 2 of 9 patients treated with 75-135 mg/m2 and in all 16 patients (Grade 3) treated with 175-275 mg/m2. Grades 1-2 nausea and vomiting occurred in about one-third of the patients treated at a dose of 105 mg/m2 or more. Taxol disappearance from plasma was IÂ»phasic;half-lives of the first and second phases after a 275 mg/m2 dose were 0.32 and 8.6 h, respec tively. The apparent volume of distribution was 55 liters/m2, and the peak plasma concentration with a dose of 275 mg/m2, which occurred imme diately postinfusion, was approximately 8 jiM. Only 5% of parent drug was excreted in the urine within 24 h. Minor objective responses were noted in one patient with gastric cancer and another with ovarian carci noma. In addition, one patient with massive ascites due to metastatic adenocarcinoma from an unknown primary had only minimal sonographic evidence of ascites for 6 months posttreatment. Neurotoxicity and leukopenia were dose limiting in this schedule. The recommended phase II trial dose is 250 mg/m2, with premedication.
INTRODUCTION One of the most important clinical and laboratory efforts designed to improve cancer treatment is the development of new chemotherapeutic agents with antineoplastic activity. We have recently completed a phase I taxol trial in which we (a) determined a dose appropriate for subsequent phase II studies, (/' ) determined the human pharmacokinetics of the drug on a 6-h infusion schedule, (c) defined the human toxicity of the agent, and (d) observed antitumor activity. The results of this study are reported here. Taxol is a novel diterpenoid originally isolated from the stem bark of the western yew, Taxus brevifolia (1). The drug is a complex ester, shown to be a taxane derivative containing a rare oxetan ring (Fig. 1), and is the first compound of this type to have antineoplastic activity against B16 melanoma, and LI210 and P388 leukemias as well as human MX-1 mammary tumor, CX-1 colon, and LX-1 lung tumor xenografts. Work at the Albert Einstein Cancer Center has demonstrated
that taxol has a unique mechanism of action. The drug interacts with microtubules in vitro and in cells. In contrast to Vinca alkaloids which inhibit microtubule assembly, taxol promotes microtubule assembly in vitro (2). Microtubules polymerized in the presence of taxol are resistant to depolymerization by cold (4Â°C)or calcium (4 ITIM),conditions known to depolymerize microtubules in the absence of taxol. Taxol decreases the critical concentration of tubulin required for microtubule assembly. Cell culture experiments have demonstrated that in fibroblasts and other proliferating cell systems exposed to taxol, abnormal bundles of microtubules form throughout the cyto plasm (2-3). In organotypic dorsal root ganglion-spinal cord cultures taxol exposure leads to the formation of unusual num bers and arrays of microtubules in neurons and satellite and Schwann cells (4-7), and binding of 3H-labeled taxol to micro tubules has been demonstrated (8-10). The drug also blocks cells in G2 and M of the cell cycle and increases the mitotic index of P388 cells (11). In addition, fibroblast cell migration is inhibited by taxol, due probably to a direct action on micro tubules, since taxol-treated cells are unable to depolymerize their microtubule cytoskeletons. These findings may be relevant to the observed antitumor activity of the drug. Because of the drug's animal antitumor activity and its unique structure and mechanism of action, taxol has been selected for phase I clinical trials. MATERIALS
Patient Selection. Patients eligible for this trial had histologically documented malignant disease other than leukemia, lymphoma, or myeloma and had failed conventional chemotherapy, or had a tumor for which no conventional therapy exists. Patients were required to have a minimum of 6 weeks' life expectancy and a minimal Eastern Cooperative Oncology Group performance status of 3. Patients known to have had acute hypersensitivity reactions to other agents were ineligible for the study. All patients had recovered from the toxicities of prior treatment and had adequate bone marrow function (WBC greater than 4,000 cells/mm3 and platelet count greater than 100,000/ iniu'). adequate liver function (bilirubin less than 1.5 mg/100 ml),
adequate renal function (creatinine less than l.S mg/100 ml), and normal cardiovascular function. Measurable disease was not required. All patients were informed of the phase I investigational nature of the study and the toxicities which might be reasonably anticipated from treatment. The study was approved by the Albert Einstein College of Medicine and Montefiore Medical Center Institutional Review Boards, and written informed consent was obtained from each patient. Study Parameters. Patients had a complete history and physical examination, complete blood count, serum biochemical and electrolytes profile, urinalysis, chest X-ray, and electrocardiogram prior to treat ment. During the treatment course, a complete blood count was ob tained 2-3 times weekly for the first 2 weeks, and once during the third week. Hepatic and renal blood tests and serum electrolytes were studied Received 5/21/86; revised 9/5/86, 1/6/87; accepted 2/3/87. weekly. Disease status was reevaluated prior to each treatment. The costs of publication of this article were defrayed in part by the payment Toxicity Criteria. Toxicities were evaluated according to the criteria of page charges. This article must therefore be hereby marked advertisement in of the Eastern Cooperative Oncology Group. Pertinent toxicity grades accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1Supported in part by grant P30CA1330-14 awarded by the Department of are defined in Table 1. In addition to standard toxicity measurements, Health and Human Services, a grant from the Chemotherapy Foundation, and a the degree of discomfort from specific subjective symptoms was re grant from the Ripple Foundation. Presented in part at the annual meeting of the corded prior to and at 3 time points after treatment using a Symptom American Society of Clinical Oncology, May 6, 1986. 2 To whom requests for reprints should be addressed, at Albert Einstein Cancer Distress Scale (12). The scale includes 13 items (nausea, frequency; Center, Montefiore Medical Center, 111 East 210th St., Bronx, NY 10467. nausea, intensity; pain, frequency; pain, intensity; appetite; insomnia; 2486
PHASE I TAXOL STUDY Table I Select Eastern Cooperative Oncology Croup toxicity criteria Eastern Cooperative Oncology Group grade ToxicityLeukopeniaThrombocytopeniaAnemiaNausea IO3Neutrophils x IO3Platelets x IO3Hemoglobin, x 1>32NoneNoneNoneNoneNone13.0-4.51.5-1.990-1309.5-10.928-31.9Nausea mlHematocrit g/ 100 %Peripheral0>4.5>1.9>130>1 and vomiting in controllableMild vomitingNeurologicalAlopeciaAllergyLocal and tractableSevere severeconstipation: paresthesias; peripheralnervefpain; mildconstipationMildTransient paresthesias; mildweaknessSevereUrticaria; obstipa tion; severe weak ness; bladder dys functionSerum
dysfunc tion; obstipation re quiring surgery; pa ralysisAnaphylaxis
rash; drug fe fever>38*C; drug broncho-spasmPain mild <38'CPain22.0-3.01.0-0.550-90<9.5<28Nausea ver
toxicityWBC O II H3C-C-0
athy ( 16). Thermal thresholds were determined using the Pfizer thermal tester (17). An elevated threshold indicated dysfunction in the smallfiber sensory pathways which mediate temperature discriminations. Pharmacological Methods. Urinary and plasma taxol concentrations were determined by a HPLC3 method developed in our laboratory. At specified intervals during and after drug administration, heparinized blood samples were obtained and plasma was prepared by centrifugation. Initial studies indicated that measured taxol concentrations in plasma did not change when samples were stored at â€”20Â°C. To prepare
TAXOL Fig. 1. Taxol, chemical structure.
fatigue; bowel patterns; concentration; appearance; breathing; cough; and outlook) listed with a S-point Likert scale. Data can be analyzed by total score or each item can be analyzed individually. Drug Information, Formulation, and Treatment Schedule. Taxol is supplied as a concentrated sterile solution, 6 mg/ml in a S-ml ampul (30 mg/ampul), in polyoxyethylated castor oil (Cremophor EL), 50% and dehydrated alcohol USP, 50%. The drug was further diluted in a liter of 5% dextrose in water prior to administration. A small number of fibers (within acceptable United States Pharmacopeia levels) have occasionally been detected in the preparation. Therefore, in-line filtra tion with a 0.2-nm filter was used with all infusions. Taxol was given as an i.v. infusion over 6 h every 3 weeks. Because of known acute hypersensitivity reactions associated with the Cremo phor vehicle (13-14), blood pressure was monitored every 15 min during the first h of the infusion and every 30 min thereafter during the remainder of the infusion. Precautions were taken (epinephrine and diphenhydramine were immediately available at the bedside) for the possibility of anaphylaxis. The starting dose for the study was 15 mg/ m2 (one-third of the low toxic dose in dogs). Doses were escalated according to a modified Fibonacci scale. A minimum of 3 patients was treated at each dose level until toxicity was identified and then 4-6 patients were treated at each subsequent level. The dose was not escalated for retreatment of a patient. Neurological evaluations were initially performed serially in all pa tients who developed neuropathic symptoms following treatment. Later in the study, such evaluations were done prior to therapy and before each subsequent treatment. This evaluation included neurological ex aminations and quantitative sensory testing. Nerve conduction studies were performed in one patient and a sural nerve biopsy was done in another. The quantitative sensory testing procedures used measure the sensory thresholds to vibratory and thermal stimuli in the dominant index finger and great toe, using a psychophysical vibration paradigm. Thresholds were determined using the Vibraton ( 15). Elevated vibration thresholds reflect dysfunction of large fiber sensory systems. Prior studies demonstrated that vibration thresholds are reliable in detecting and following the course of chemotherapy-induced peripheral neurop
samples for HPLC analysis, 0.4 ml of plasma was combined with 1.0 ml of ice-cold acetonitrile (20 min; 5Â°C).The supernatant was evapo rated to dryness under reduced pressure, and the sample was resuspended in 50 ^1 methanol immediately prior to HPLC analysis. Urine samples, collected during the 6-h infusion and for 24 h postinfusion, were prepared in the same manner. Samples were analyzed by HPLC using a Whatman Partisi! 10 ODS3 column (4.6 x 250 mm) at 40Â°Con a Hewlett Packard HP1090 liquid Chromatograph device equipped with a diode array detector. Detection was at 227 nm. The mobile phase of 1:1 CH3CN:H2O (containing 0.5% HjPCM was linearly increased to 85% CH3CN over 10 min. Plasma samples from patients treated with taxol contained a peak with a retention time of 5.2 min which was absent from blood samples drawn immediately prior to taxol administration. As evaluated by the diode array detector, this peak represented a single compound with a UV spectrum identical to that of taxol. Taxol concentrations were calculated from HPLC runs using an HP 3390A integrator by comparison with a standard curve. Taxol standard curves were found to be linear over a concentration range of 0.7-100 fiM. The extraction efficiency of taxol from plasma was determined by spiking plasma samples from each patient with purified taxol to a final concentration of 2 /IM;these were analyzed with each patient's unspiked samples as described above. Extraction efficiency was 76 Â±2.8% (SE; n = 22 samples). Pharmacokinetic parameters were calculated using a multicompartmental model (18). The log plasma concentration versus time curves were fitted to biexponential equations and the half-lives (tv,) calculated by dividing 0.693 by the rate constant for each phase. The total AUC was calculated using the linear trapezoidal method with extrapolation to infinity. Total plasma clearance was calculated by dividing the dose by the AUC, and renal clearance was calculated by dividing the quantity of taxol excreted in the urine (0-24 h) by the AUC (0-24 h). The volume of distribution and the mean residence time were calculated from the area under the moment curve (19). In Vitro Cell Culture. Pleural and peritoneal effusion fluids with malignant cells were obtained under sterile conditions from 2 patients (metastatic melanoma, metastatic colon carcinoma) prior to the taxol infusion and again at the end of the infusion. Viable and nonviable tumor cells were immediately separated by Ficoll-Hypaque density 3The abbreviations use are: HPLC, high-pressure liquid chromatography; AUC, area under the curve: SDS, subjective distress scale.
gradient centrifugation and cultured in KI'M I 1640 medium (GIBCO) supplemented with 10% fetal bovine serum (GIBCO), 0.3% L-glutamine, 100 Mg/ml streptomycin, and 100 units/ml penicillin in a humid ified atmosphere of 5% CÃ›2 in air. Cells obtained from pre- and posttaxol samples were cultured at identical cell concentration (1.5 x IO5cells/ml) in 24-well plastic plates (Corning). The effect of taxol on cell growth in culture was studied by adding 2 x 10~"-2 x 10~7 M of drug dissolved in methanol to the culture medium after freshly inocu lated cells from pretaxol samples had been allowed to adhere. To control cultures, the appropriate concentrations of methanol (maximally, 2%) were added. At indicated days of culture, cell morphology and the degree of confluency were evaluated using an inverted microscope (Nikon).
RESULTS Eighty-three courses of taxol were administered to 34 patients enrolled in this study. Demographic characteristics of the pa tients are included in Table 2, and dosing information is shown in Table 3. Toxicity. Acute hypersensitivity reaction, which occurred in 3 of the first 4 patients treated, was the most serious acute toxicity noted in this trial. All reactions occurred within the first few minutes of the second drug infusion (which was given Table 2 Demographic data for 34 study patients
3 weeks after the first infusion). Epinephrine, diphenhydramine, dexamethasone, and/or aminophylline were required to treat the reactions. Retreatment with taxol was attempted with 2 patients after premedication with dexamethasone and diphen hydramine. A similar and equally severe reaction recurred in one but not the other. In an attempt to prevent further reactions, the duration of the infusion was extended to 6 h with a pre medication regimen of dexamethasone, diphenhydramine, and cimetidine added. One additional patient experienced mild dyspnea 24 h after treatment following her second course (275 mg/m2). Diphenhydramine p.o. was given every 6 h for 24 h following the third course and dyspnea did not recur. Two patients developed skin rash after taxol given with premedication. One developed a papular neck rash 4 days after treatment (135 mg/m2) which extended to her face during the following week and then resolved. Another patient developed a thigh rash 2-3 days after taxol administration (230 mg/m2) which resolved without treatment in 10 days. Both minor reactions occurred with the first taxol course and neither patient was retreated. The other 28 patients experienced no allergic reactions in 69 courses. The taxol administration schedule and premedication regimen are shown in Table 4. Hematological toxicity manifested as leukopenia and neutro penia was observed at doses of 175 mg/m2 and greater. Eight patients (20 courses) had leukopenia of Grade 3 or 4. Nadir day 11 (mean) with recovery on day 18 (mean). The mean WBC nadir count was 2.3 x lO3/^! with a mean nadir absolute neutrophil count of 0.68 x 103/Ml-Platelet
of WBC occurred on patients14103231231111111221624195
(range):Median age, y CooperativeOncology Eastern performancestatus Group (range)Primary lumorPrior
counts and hematocrit were not affected by the treatment. Leukopenia was variable at all doses (175 mg/m2 and greater) and among courses of treatment for each patient. As examples, one patient treated at 175 mg/m2 who received 4 courses of
carcinomaBreast squamous cell adenocarcinomaColon adenocarcinomaGastric adenocarcinomaAdenocarcinoma otherwisespecifiedRenal not
treatment had Grades 4, 0, 2, and 1 leukopenia with each course, respectively. Another patient treated at 275 mg/m2
received 2 courses of treatment, and had Grades 4 and 1 leukopenia, respectively. Neurotoxicity, which occurred in 5 patients after 9 courses cancerNonsmall cell lung of therapy, was the dose-limiting toxicity. Four of 5 patients cancerSarcoma cell lung treated at 275 mg/m2 experienced Grade 2-3 neurotoxicity. not otherwise speci fiedEsophageal Neuropathic symptoms developed 24-72 h following treatment squamous cell car and included tingling and numbness in the hands and feet. One cinomaCervix patient also experienced perioral numbness. All 5 patients squamous cell carci nomaRectal experienced spontaneous pain which presented as burning, par adenocarcinomaOvarian ticularly in the feet and often associated with hyperpathia. adenocarcinomaNoneRadiotherapyImmunolherapySurgeryChemotherapy1-2 Neurological examination revealed distal sensory loss to large (vibration, proprioception) and small (pin prick, temperature) fiber modalities with a glove and stocking distribution. All 5 patients had absent ankle jerks, and one became totally areregimens>2 flexic. The motor examination was intact in all patients. Quan regimensNo. titative sensory testing revealed significant elevations in vibramore than one category. adenocarcinomaMelanomaSmall
" Some patients are included in
Table 4 Treatment and premedication schedule
Table 3 Dose escalation schedule
Route of ad minis Dose (mg) tration
of of Dose (mg/m2)Â«1530455075105135175200230275No. patients33123335335No.courses675483411111212 Premedication Dexamethasone Diphenhydramine Cimetidine
tion thresholds in the 5 patients and thermal threshold eleva tions in 2. Nerve conduction velocities in one patient showed slowing in sensory nerves with relative sparing of motor nerves. Sensory symptoms resolved in 4 patients several months after treatment was discontinued. Reflexes recovered fully in the patients who had developed areflexia. A sural nerve biopsy was performed on one patient treated at 275 mg/m2 who experienced Grade 2 neuropathy which persisted 3 months after the discontinuation of treatment. The biopsy revealed no obvious disarray or abnormal aggregation of microtubules in the axons or Schwann cells, as observed in tissue culture studies with taxol. An occasional thinly myelinated axon suggestive of remyelination was observed. Grade 3 alopecia was observed in all patients treated at 175 mg/m2 or greater. Hair regrowth occurred approximately 6-8 weeks after treatment was discontinued. Mild nausea and vom iting were observed in about one-third of the patients at dose levels of 105 mg/m2 or greater. Nausea occurred during the day of treatment and/or nausea occurred with 1-2 emetic episodes after treatment. One patient treated at 275 mg/m2 developed Grade 2 stomatitis with each of her 3 courses of treatment which resolved without complications before each retreatment. Local toxicity occurred as Grade 2 cellulitis if large volumes (greater than 50 ml) of the taxol solution were infiltrated at the i.v. site. Local tissue toxicity has been reported with other agents solubili/ed in Cremophor. SDS data were collected during the first course of treatment for 29 patients (20). Repeated analyses of variance revealed no significant change in total SDS scores during treatment. Anal ysis of each SDS item revealed no significant change in preand posttreatment scores except for the item entitled "outlook,"
larger than total body water. This result suggests that taxol may be extensively bound to plasma proteins and other tissue com ponents. Greater than 97% of taxol has been shown to be bound to human serum by equilibrium dialysis (21). Drug urinary excretion occurred primarily during the infusion interval in average quantities ranging from 4.3-6.6% of the total dose administered (Table 5). The observed renal clearance of taxol ranged from 2.4-14.0 ml/min/m2. These data suggest that the kidney was not the primary route of drug elimination. Ascites samples from one patient were obtained after treat ment with taxol, 175 mg/m2 (Fig. 5). Drug was not detected in ascitic fluid during the 6-h i.v. infusion but was measurable shortly after the end of the distributive phase in plasma (h 78). The ascitic fluid taxol concentration increased for several h thereafter and reached a maximum concentration of 0.25 MM. It then stabilized at a level approximately 40% above that in plasma for at least 12 h. Tumor Responses. Although measurable disease was not a requirement for entry into the study, tumor measurements were recorded prior to and after treatment whenever possible. Two colon cancer patients who had progressive disease prior to taxol had stable disease after treatment. One patient treated with 5 courses at 50 mg/m2 had stable disease for 7 months. At that time she underwent laparotomy in preparation for i.p. chemo therapy, at which time significant tumor necrosis was noted. The other patient, treated with 7 courses at 200 mg/m2 had
which significantly improved during the treatment course (P < 0.001). Toxicities observed in this study are summarized in Table 5. Pharmacology. Taxol pharmacokinetics were studied in 12 patients. Fig. 2 illustrates the plasma pharmacokinetics of 3 patients treated with a dose of 230 mg/m2. Drug plasma con centrations increased throughout the 6-h infusion and began to decline immediately upon cessation of the infusion. Plasma disappearance curves were biphasic, with an a and ÃŸ iVl(average of all doses) of 0.42 and 8.4 h, respectively (Table 6). Peak plasma concentrations ranged from 2-10 fiM and were propor tional to the taxol dose (Fig. 3). AUC, which ranged from 1664 h mg/liter was also proportional to dose. A taxol dose of 275 mg/m2 resulted in exposure to drug levels at least 2-fold greater than lower doses.
Plasma decay curves for all dose levels studied are shown in Fig. 4. Neither the ÃŸphase of elimination nor the mean resi dence time varied with dose. The steady state volume of distribution of taxol averaged approximately 60 liters/m2 (Table 6), a value substantially
stable disease for 4.5 months with a 50% decrease carcinoembryonic antigen. Complete disappearance sions for 1 month occurred in a patient with gastric treated with 3 courses at 75 mg/m2, while no change
in plasma of skin le carcinoma was noted
in his abdominal mass. A minimal response in an abdominal mass with a 30% decrease in CAI25 and a partial reduction of a pulmonary* nodule lasting 6 weeks was noted in a patient with ovarian cancer who received 3 courses at 275 mg/m2. An excellent partial response lasting 6 months occurred in a patient with adenocarcinoma of unknown origin treated with 9 courses at 230 mg/m2. He presented with massive ascites and weight loss. Following treatment his ascites was detectable on sonogram only and his weight returned to normal. Three additional patients had subjective pain improvement following treatment. Clinical response data are summarized in Table 7.
Table 5ToxicityDose (mg/m2)ToxicityAllergic re 1(3);*1(4)0/60/62/6; 2(3)0/70/70/70/70/70/745/500/90/90/91/9; actionMarrowsuppres 1(1)0/83/8;
Animal toxicology studies of taxol were conducted in CD2Fi mice (i.p. administration), Sprague-Dawley rats (i.p.), and bea gle dogs (i.v. infusion) (22). In the rodent species, the i.p. route was selected due to dose volume constraints imposed by limited compound solubility and vehicle toxicity. The rat and dog studies were done with either a single dose or on a 5-consecutive days' dose schedule, while the mouse toxicity study was done with the 5-consecutive days' schedule only. In the rodent i.p.
Fig. 2. Plasma pharmacokinetics of taxol. Taxol was administered as a 6-h constant i.v. infusion (time 0-6) at a dose of 230 mg/m:. Plasma concentrations were determined at indicated times as described in the "Materials and Methods." Values, mean Â±SE (bars) for 3 patients.
Effect of Taxol on Tumor Cell Growth in Vitro. Tumor cells isolated from pleural or peritoneal fluid grew as monolayers in culture. While cells isolated from pretaxol samples reached confluency at day 7 postinoculation, cells from fluids obtained immediately after the end of the taxol infusion showed retarded cell growth and did not achieve confluency until day 14 of culture or later. As seen in Fig. 6, the morphology of cells obtained at the end of taxol infusion was more fibroblast-like compared with the epithelial appearance of cells obtained before taxol. When taxol was added to the culture medium of cells grown from pretaxol samples, a dose-dependent effect on cell growth and morphology was seen in that with increasing drug concentrations (10~'Â°-10~7M) cells increasingly lost their ca pacity to adhere and were found rounded-up in suspension. At the highest taxol concentration tested (10~7 M), greater than 80% of cells became nonadherent within 2 days of exposure to the drug. These suspension cells when recultured in taxol-free medium did not regain capacity to adhere and were no longer viable 1 week postdrug exposure. At 10~7 M taxol, a 10-min exposure of adherent cells was sufficient to cause these irrever sible morphological changes. DISCUSSION Thorough delineation of the toxicity in animals of a new agent is a prerequisite for phase I clinical trials.
studies, females were slightly less sensitive than males to taxol based upon a comparison of the low dose 10 and low dose 50 values. Both sexes had an equivalent response at the low dose 90 in all cases. Toxicity was evaluated in beagle dogs using an i.v. infusion given both on a single dose and a daily x 5 schedule. In the above test systems, the major toxic effects of taxol were most evident in tissues with high cell turnover: hematopoietic; lymphatic; gastrointestinal; and reproductive (male ro dents only). Drug-related lesions were dose related and revers ible, with the exception of mandibular lymph node inflamma tion (rats) and tonsilitis (dogs). Hematopoietic toxicity was evident in all 3 species although the cell lineages affected and severity of toxicity varied among species. Dogs developed anemia, reticulocytopenia, thrombocytopenia, and leukopenia in the lethal dose-toxic dose high range. Effects at the toxic dose-low and highest nontoxic dose were minimal and readily reversible. Effects on systems other than the hematopoietic, lymphatic, reproductive, or gastroin testinal were relatively minor. In comparing the effect of sched ule, it is apparent that the toxicities of taxol are cumulative over a 5-day dose schedule. The vehicle, polyoxyethylated castor oil (Cremophor EL), which has significant toxicity itself, seems much better tolerated in the repeated dose regimen and has no apparent cumulative toxicity. The vehicle administered as a large volume single dose in dogs had unpredictable and occasionally lethal effects. Dogs are sensitive to the hypotensive effects of the Cremophor com ponent of the vehicle. The acute hypersensitivity reactions observed in this study may be related to the Cremophor vehicle rather than to taxol itself. Similar reactions have been reported with other drugs solubilized in Cremophor (13-14). The mechanism of the hy persensitivity reaction is unknown, but it is thought not to be immunological in nature. The characteristics of the reaction
Table 6 Pharmacokinetic parameters of 6-H continuous i.v. infusion of taxol
Fig. 3. Relationship of peak plasma concentration (left) and AUC (right) to dose administered. Taxol was administered at doses from 175-275 mg/m2, and plasma concentrations were measured as in Fig. 2. Points, data from an individual patient. Correlation coefficients for both curves were significant, at P < 0.05. CO/VC, concentration; /, liter.
6weeksNoneNoneNoneNonePartial response x 1751530,20075135,230ResponseNoneNoneNone(a) cancerSquamousUnknown cell lung originAdenoUnknown originNo.
6months response x at 230 mg
This toxic effect may be related to the ability of taxol to promote microtubule accumulation in neural tissue (4-7). It is of interest to note that neuropathy was not noted in one patient who received 9 courses of treatment at 230 mg/m2. Therefore, serial
3456 TIME (hr)
Fig. 4. Comparison of plasma disappearance of taxol at 4 dose levels. Taxol was administered as indicated in Fig. 3. Plasma decay curves upon completion of infusion are 175 (O), 200 (â€¢),230 (A), and 275 (A) mg/m2. Curves, mean of 2-4 patients.
20 i TIME(hr) Fig. 5. Comparison of taxol concentrations in plasma and ascitic fluid. The taxol dose was 175 mg/m2. At the indicated times, taxol concentrations in plasma (â€¢)and ascitic fluid (O) were determined.
are reminiscent of the acute reaction related to iodinated con trast media, which results from direct histamine release from tissue and circulating basophils (23-24). The premedication regimen of dexamethasone, diphenhydramine, and cimetidine was utilized to counteract this complication (25). On the basis of this phase I trial, the dose-limiting toxicities of taxol on this schedule appear to be neuropathy and leukopenia. Neuropathy was moderate to severe only at 275 mg/m2 and was irreversible in one patient. It is best described as a predominantly sensory neuropathy often associated with pain.
exposure at high dose may not always result in neurotoxicity. Leukopenia occurred on day 11 (mean) with full recovery by day 18 (mean). It was not associated with thrombocytopenia or anemia. The incidence and severity of leukopenia was not increased in patients who had received numerous prior treat ment regimens. Acute hypersensitivity reaction was frequent and severe prior to the institution of premedication and prolongation of the infusion time. After those measures were implemented only 3 subsequent mild reactions occurred with the next 70 treatments. Although disturbing, the frequency and quality of the reactions with premedication is acceptable. With the exception of hair loss, the other side effects associ ated with the treatment were mild and easily tolerated. These observations were substantiated by the subjectively reported SDS scores which revealed no increase in the degree of discom fort from specific symptoms posttreatment. In addition, inclu sion in the trial had a positive effect on the patients' future outlook score (20). The plasma concentrations of taxol attained in patients on this study were comparable to those required for the ant Â¡prolif erativi- and microtubule-stabilizing effects of taxol in vitro. Purified microtubules assembled in the presence of 10 pM taxol for 30 min were found to be resistant to depolymerization, while those assembled in the presence of 5 MM taxol were partially resistant (26). More subtle effects on microtubule length were observed at taxol concentrations as low as 1 //M (26). Taxol binds to tubulin in microtubules at an approximate saturation ratio of 1 mol taxol/mol polymerized tubulin dimer (9). The Km for binding of 3H-labeled taxol to microtubule protein in vitro was 0.8-2 ^M, a concentration of drug readily achieved in the plasma of patients treated at doses ranging from 175-275 mg/m2 in a 6-h i.v. infusion. It should be noted, however, that this binding was easily reversible. This suggests that a longer duration of exposure may increase the efficacy of taxol as an antitumor agent. Consequently, we have begun a 24-h infusion taxol phase I trial (21).
Fig. 6. Photomicrographs of confluent monolayers formed by tumor cells obtained from pretaxol effusion samples by day 7 of culture (A and O in comparison to the much scarcer adherent layers formed by cells obtained postinfusion oftaxol after the same time of in vitro culture (B and /Â».Cells were isolated from the pleural effusion of a patient with metastatic melanoma (A and lÃ¬) and from the ascites fluid of a patient with metastatic colon carcinoma (C and />). Original magnification, X400.
Objective responses occurred at several dose levels, primarily in adenocarcinomas. Taxol represents a new class of potential antineoplastic agents. The results of this trial suggest that taxol can be administered to patients in doses that may have antineo plastic activity with relative safety. Phase II trials with this schedule are recommended, especially in patients with adeno carcinomas. Phase II trials in melanoma are equally warranted, since the drug is active against the B16 melanoma model, and in vitro activity against tumor cells from the only melanoma patient in the study was noted. The recommended phase II dose with this schedule is 250 mg/m2 with premedication. ACKNOWLEDGMENTS We appreciate the effort of the many physicians and nurses who provided excellent care for the patients in this study, and we are grateful to the numerous physicians who referred patients to us for enrollment.
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Phase I Clinical and Pharmacokinetic Study of Taxol Peter H. Wiernik, Edward L. Schwartz, Janice J. Strauman, et al. Cancer Res 1987;47:2486-2493.
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