Phase I and Pharmacokinetic Study of Taxotere

[CANCER RESEARCH 53, 1037-1042. March I. 1993] Phase I and Pharmacokinetic Study of Taxotere (RP 56976; NSC 628503) Given as a Short Intravenous Infusion Jean-Marc Extra, FrÃ©dÃ©riqueRousseau,RenÃ©Bruno, Michel Clavel, Nathalie Le Bail, and Michel Marty1

Sen-ice d'Oncologie medicale. HÃ´pital Saint-Louis. Paris 75010 Â¡J-M.E., F. R.. M. M.]; Institut de Biopharmacie, RhÃ´ne-Poulenc Rarer Recherche-DÃ©veloppement. Antony 92I6S Â¡K.B.I: Centre LÃ©onBÃ©rard,Lyon 69008 Â¡M.C. I: and RhÃ´ne-Poulenc Rarer Recherche-DÃ©veloppement. Antony 92165 Â¡N.Le B.Â¡.France

ABSTRACT Toxicology studies have been performed by i.v. route in mice and dogs. The minimum toxic dose in dogs is 15 mg/m2. Doubling this Taxotere (jY-debenzoyl-A'-/ert-butoxycarbonyl-10-deacetyl Taxol; RP dose (30 mg/m2 = 10% lethal dose in mice) causes no lethality in dog. 56976; NSC 628503) is a semisynthetic analogue of Taxol. It is twice as Toxic side effects consisted of reversible leukoneutropenia in dogs active in inhibiting tabuline depolymerization and has a better in vivo activity on B16 melanoma, with responses in advanced colon 38 and PO3 and mice. In dogs, other toxicities include emesis, diarrhea, mucosal adenocarcinoma. Sixty-five patients (49 women, 16 men), with a median ulcÃ©rations,symptoms of cardiovascular shock, hair loss, and revers age of 57 years, received 248 courses of Taxotere given as a 1-2-h i.v. ible biochemical changes (transient elevation of cholesterol and trig infusion every 2 or 3 weeks. Ten distinct dose levels from 5 to 115 mg/m2 lycÃ©rides).In mice, dose-related delayed and reversible peripheral were studied. Dose-dependent, reversible neutropenia was the limiting neurological symptoms were observed. Death of the animals seemed toxicity. Delayed and cumulative skin reactions occurred beyond 70 mg/ to be due to acute cardiorespiratory side effects in mice, and digestive in-. Alopecia was observed in the majority of patients beyond 70 mg/m2. tract lesions with myelotoxicity as a possible contributing factor in Four partial responses were achieved in patients with ovarian carcinoma, dogs. A pharmacokinetics study in mice shows a biphasic drug dis breast carcinoma, small cell lung cancer, and carcinoma with unknown position, with half-lives of 0.1 and 1.1 hour, a linear profile, and good primary. The pharmacokinetics of Taxotere, determined in 23 patients receiving 20 to 115 mg/m2, was linear. At the highest doses, the Taxotere tumor retention (25). plasma profile was typically triphasic, with a terminal half-life of 13.5 We undertook a phase I study, using a starting dose of 5 mg/m2, 7.5 (SD) h, a plasma clearance of 21.1 Â±5.3 liters/h/m2, and a distribution one-third of the minimum toxic dose in dogs (one-sixth of the 10% volume of 72 Â±40 liters/m2. AUC correlated with the percentage decrease lethal dose in mice), and a pharmacokinetics study. This dose was of neutrophils in a sigmoid K,11Â¡txmodel.The renal excretion of unchanged selected because of similar qualitative side effects observed in mice Taxotere was very low (<5% of the dose). The recommended dose for and dogs with Taxol and Taxotere, the known maximum tolerated phase II trials with this schedule is 100 mg/m2 every 3 weeks. dose of Taxol in humans, and the expected twice lower toxic doses with Taxotere. INTRODUCTION Taxol is a plant product extracted through a lengthy fermentation of MATERIALS AND METHODS the trunk bark of the western yew Taxus brevi/olia (1). This new antitumor agent is a mitotic spindle poison that has a broad spectrum Patient Population. To be eligible, patients had to fulfill the following of preclinical activity. It exerts its cytotoxicity by a unique mechanism criteria: histologically proven malignancy not amenable to standard therapy; an of action on microtubule structure and function (2-4). Phase I and II age between 18 and 75 years; a life expectancy of at least 12 weeks: and a studies have shown that the limiting toxicity of Taxol was neutrope minimum interval of 4 weeks since prior chemoradiotherapy. Other inclusion nia; other main toxicities were anaphylactoid reactions, mucositis, criteria were normal bone marrow, hepatic and renal function, and absence of alopecia, neuropathy, and cardiac disturbances (5-12). Taxol has neurological or psychiatric symptoms. Patients had to give written informed shown, in phase II clinical trials, encouraging results in ovarian and consent. breast cancer patients (13-18). One major obstacle in the development Medical histories and physical examinations were completed on the day of therapy. Biological tests were performed before each Taxolere administration, of Taxol is limited drug supply (19). An analogue of Taxol, Taxotere,2 was obtained by semisynthesis and weekly thereafter. They included coagulation tests, determinations of serum electrolytes, creatinine, cholesterol, triglycÃ©rides, liver function tests, from 10-deacetyl baccatin III, extracted from the needles of the and complete blood cell counts with differential. Electrocardiograms and chest European yew tree Taxus boccata L (20, 21). As Taxol, Taxotere X-rays were performed monthly. Blood pressure and pulse rate were contin exerts its cytotoxic properties through the inhibition of microtubule uously monitored for 24 h during each Taxotere administration. Other inves depolymerization and promotion of tubulin assembly (22). Taxotere tigations were conducted according to the individual patients' symptoms. was evaluated for antitumor activity against a variety of transplantable Toxicities were evaluated according to the WHO criteria (26), except for tumors in mice; B16 melanoma, pancreatic ductal adenocarcinoma 03, neurotoxicity. for which National Cancer Institute/Common Toxicity Criteria and colon adenocarcinoma 38 and 51 were found to be highly sensi grades were used. The maximally tolerated dose was initially defined as the tive to Taxotere, even at advanced stages (23). Compared with Taxol, dose that would lead to grade 3 or 4 toxicity with clinical sequelae or side Taxotere is slightly more active as a promoter of tubulin polymeriza effects considered as subjectively intolerable by more than 50Vr of the patients tion, 2.5-fold more potent in inhibiting the replication of J774.2 and treated at this dose level. When measurable tumor sites were found they were assessed every two P388 cells, and 5-fold more potent in inhibiting the replication of courses by appropriate means. Tumors markers, when present, were deter J7.T1-50 Taxol-resistant cells (24). mined prior to each course. Drug Supply and Treatment Plan. Taxotere was supplied by RhÃ´ne- Received 8/5/92; accepted 1/19/93. Poulenc Rorer laboratories in vials containing 15 mg/ml in 507r polysorbate 80 The costs of publication of this anicle were defrayed in part by the payment of page (Tween 80) and 50% dehydrated alcohol. The vials were reconstituted just charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. prior to use in 50 cc of 5% dextrose in water, and the amount of Taxotere to 1To whom requests for reprints should be addressed, at Service d'Oncologie medicale. be administered was further diluted in 5% dextrose in water, so that the HÃ´pitalSaint-Louis. 1. Avenue C. Vellefaux. Paris. 75010, France. -The abbreviations used are: Taxotere, /V-debenzoyl-/v'-/i'rr-butoxycarbonyl-10- maximum Taxotere concentration was 0.3 mg/ml. This procedure was followed deacetyl Taxol (RP 56976; NSC 628503); HPLC. high-performance liquid chromatogra- to ensure that the polysorbate 80 concentration would not exceed 1% (a phy; AUC, area under the concentration-time curve from time 0 to infinity; Vâ€ž.steady- concentration inferior to that inducing hemolysis in dogs; internal report); thus state distribution volume. both the infusion volume and duration were doubled at doses over 70 mg/m2. 1037

To further decrease the quantity of polysorbate 80 and to eliminate the Table 1 Patients characteristics and tumor types (n = 65) ethanol, a second formulation has been developed, with 40 mg/ml in 100% of Sex(F/M)Median polysorbate 80. The concentration of polysorbate 80 is lowered by about 30%, (range)WHOage (35-70)0 and a higher concentration of Taxotere ( 1 mg/ml in 5% dextrose in water statusNo.performance =81 solution) can be administered to the patients. After completion of dose esca =402= lation with the first formulation, nine patients have received the second for 17652 mulation (three patients at each of three upper levels) as a 1-h infusion, and, since there were no differences in toxicity (data not shown), the data were therapyNo.of patients withprior of previous regime median(1-6)Tumor (range)49/1657 pooled for all patients, whatever the formulation used. No pretreatment medication to prevent gastrointestinal toxicity or anaphy- TypesOvaryBreastSarcomaKidneyLungHead lactic reaction was given. The drug was to be given at intervals of 2 weeks and then at an interval of 3 weeks when side-effects were observed (in this study at doses greater than 55 mg/m2). No dose reduction or intrapatient escalation was planned. Treatment was stopped in cases of severe toxicity, progression of disease, or patient refusal. A cohort of 3 patients was studied at each dose level until significant toxicity was observed; in this case, 3 new patients were andneckColon281373322EsophagusUterusMelanomaBladderStomachLiverUnknown primary included before proceeding to a new dose escalation. A modified Fibonacci scheme was used for dose escalation. Pharmacokinetic Study. Blood and urine samples for pharmacokinetic Table 2 Dose escalation studies were obtained from 23 patients (25 courses). Blood samples were collected before infusion, 30 min after the beginning of infusion, every hour if Level12345678"9Â«10"Dose(mg/m2)510203040557085100115%increase10010050303030202015Patients(Ã©valuable)33644651510965Courses8101616142419762540248(8)(8)(16)(16)(10)(24)(19)(70)(18)(39)(228) infusion lasted more than 1 h, 5 min before the end of infusion, and, thereafter, 5, 10, 20, 30, 60, 90 min and 2, 3, 4, 6, 8, 12, and 24 h postinfusion. Urine was collected in timed aliquots for 24 h after administration. Plasma and urine samples were kept frozen at -20Â°C until analysis. Taxotere concentrations in plasma and urine were determined by a rapid, selective, and reproducible HPLC assay with UV detection. The method in volves a solid-phase extraction (C2 ethyl microcolumns), using the Advanced Automated Sample Processor (Varian), followed by reverse-phase HPLC. The validated quantitation range is 10-2500 ng/ml in plasma and 25-2500 ng/ml in urine with an interday coefficient of variation less than or equal to 11%. " Three patients received the second formulation. Pharmacokinetics parameters were estimated by nonlinear least-squares weighted regression analysis (SIPHAR version 4; Simed, CrÃ©teil,France). Individual plasma concentrations were fit to two- and three-exponential equa and by patients (maximal grade) is depicted in Table 3. Grade 4 tions (corresponding to two- and three-compartment pharmacokinetic models). neutropenia was not observed until 55 mg/m2, except for one heavily The best model was chosen on the basis of the Akaike information criterion. pretreated patient, who died of pulmonary infection at day 22 after Fitted parameters (coefficients and exponents of exponential equations) per treatment given at 20 mg/m2, with grade 4 neutropenia and thromb- mitted the computation of the following pharmacokinetic parameters: half- ocytopenia. Postmortem bone marrow biopsy was consistent with lives; AUC; total plasma clearance; and VS5. In order to assess the pharmacokinetic/pharmacodynamic relationships of Taxotere, the percentage secondary myelodysplastic syndrome. decrease in neutrophil count was calculated according to the formula: This was the only toxic death in this study. Grade 4 neutropenia occurred in 40% of patients treated at 70 mg/m2, in 73% of patients Pretreatment count â€”¿nadircount at 85 mg/m2, in 75% of patients at 100 mg/m2, and in 89% of patients % decrease = x 100 Pretreatment count at 115 mg/m2. Neutropenia occurred between the fifth and the eighth day after Taxotere infusion. Its median duration was 7 days (range, and was related to AUC according to a sigmoid Â£maxmodel (27) as follows: 3-14 days). Â£â€žâ€ž(AUC)( Despite this incidence of grade IV neutropenia, only three patients % decrease = (AUC50)' + AUC* had to be readmitted for neutropenic fever; it was resolved after i.v. antibiotherapy. In only 2 patients did treatment have to be postponed Nonlinear least-squares regression using SIPHAR was used to estimate the because of incomplete leukocyte recovery. AUC50 (the AUC that produces 50% of the maximum effect) and k (sigmoidic- Thrombocytopenia occurred in only 7 patients (2 with grade 3-4); ity coefficient). The maximum effect (EmaJ was assumed to be a 100% it was not clearly dose related. Of 62 Ã©valuablepatients, 35 experi decrease Â¡nneutrophil count. enced anemia; since it was mainly observed after the first and second courses, it was considered to be related more to previous treatments than to the dose of Taxotere. One patient, with grade IV anemia, had, RESULTS prior to inclusion, cisplatinum-induced renal insufficiency (serum Sixty-five patients received 248 courses of Taxotere (median per creatinine, 130 umol/liter) with a low serum erythropoietin level. patient, 3; range, 1-9). This population included 49 women and 16 Nonhematological toxicities are listed in Table 4. Alopecia was men with a median age of 57 years (range, 35-70 years). As shown in dose related and appeared at 55 mg/m2. In 18 patients (34% of Table 1, an important proportion of patients had ovarian adenocarci- Ã©valuablepatients), alopecia was sudden and complete, with the loss noma. Prior to inclusion, all patients had received a median of 2 of all body hair, including axillary and pubic hair, eyelashes, and chemotherapy regimens (range, 1-6). Ten distinct dose levels from 5 eyebrows. Generally, alopecia occurred in the third week after the first to 115 mg/m2 were studied (Table 2). At the three upper dose levels, infusion. heavily pretreated patients (>2 chemotherapy regimens) were not Neurological toxic side effects were not observed at doses below 85 included. mg/m2, except for one patient. Eleven patients had grade 1-2 revers Toxicity. The main dose-limiting toxicity was a dose-dependent, ible paresthesias, and/or abolition of osteotendinous reflexes: 5 of 11 reversible, noncumulative leukoneutropenia. Neutropenia by courses had preexisting sensory symptoms related to platinum exposure. This 1038

Table 3 Neutmpenia gradeseveretoxicity by patient with most cycleDosi" No- of. WHO grade of neutropenia by recordedNo Ã©valuable(mg/m2) ofpatients (%)5 cycles 0 1 2 3 4 (%)3 0 1 2 3 4 8810 33 8820 3641 (6)30 16 13 2 1" (17)4 1Â° 1640 16 43 233255 10 16 2 (2l)70 24 4 7 3 5 5 (17)5 2 31 (16)85 19 81433 (40)15 1 2 2 (56)100 70 7 6 18 39 (73)8 1 3 11 (61)115 18 2 1 4 11 (75)9 26 (59)Total 39 5 2 9 23 (89)62 1 8 (36)" 228 59 27 19 41 82 (47)rest, 14 3 4 12 29 Neutropenia resulting indeath.Table

patientsexperiencedwere observed in 5 patients at the highest doses. Seven 4 Nonheniatttlogical toxiciliesNo. within 48 h of infusion anaphylactoid cutaneous mani of No. of patients festationsreactionswere manifested by pruritus or rash (Table 4); these WHOToxicity Dose No. of patients with with 3Alopecia (mg/m2) patients grade 1-3 grade generallyafternot clearly related to the dose of Taxotere and occurred 5-70(17)85 29 6 (20) 5 infusions.Otherthe first infusion, without worsening with further (73)100 II II (100) 8 andliver toxicities, such as gastrointestinal toxicity, mucositis, 6 6(100) 2 (33) significantbradycardiatoxicity, were uncommon and rarely severe. No (43)Neurological 115 7 6 (86) 3 (<50/min) or cardiac rhythm disturbances were regis 5-70085 31 1 (3) tered duringinfusion.Pharmacokinetics. 15 3 (20) 0 1000115 8 2 (25) werequantitated Plasma and urine levels of Taxotere 0Cutaneous 9 5 (55) detectedin in 23 patients (25 courses). No metabolites were doses(5the conditions of our assay in 2 patients receiving the lower 5â€”70085 1 1 0 (0) limitofand 10 mg/m-), Taxotere levels being below the quantification 2(13)100 15 9 (60) 0115 8 3 (38) 70mg/m2the assay very early after the end of infusion. Between 20 and 1(11)Nausea-vomiting 9 6 (67) butone (n = 9 patients), plasma disappearance was biphasic in all (2)Asthenia " (15) 1 mg/m2;npatient, at 70 mg/m2. At subsequent dose levels (85-1 15 9 (13) 2 (3) = 14 patients), triphasic profiles were observed. Typical plasma Anaphylactoid reactions 7 (11) 0 concentration-timeand100 profiles from two patients, who received 55 MucositisODiarrhea 6 (IO) (2)Dysgeusia 5 (8) 1 Pharmacokineticparametersmg/m2, respectively, are illustrated in Fig. 1. 4 (6) 0 5.Peak are summarized in Table 0ConjunctivitisLiver 2 (3) 0Headache 1 (2) tovariationplasma levels were poorly related to dose, due in part 0toxicity 1 (2) between0.92in infusion duration (actual infusion times varied pharmacokinetics.AUCand 2.5 h). However, consistent with linear mg/m2)toincreased in proportion to dose from 0.96 ug X h/ml (20 115mg/m2appeared to be dose related, since 5 patients of 9 receiving 5.2 ug X h/ml (115 mg/m2), and total plasma clearance was inde experienced paresthesias. However, its severity was not cu pendent ofdose.The mulativepatients.Cutaneous in these theinsufficientapparent dose dependence of terminal r,/2 was related to toxicity was peculiar, unpredictable, and sometimes dis anyI.EÂ«4,sensitivity of the analytical assay, which precluded abling. It led to treatment discontinuation in 4 patients (with cumu lativereduction(2 doses of 425, 485, 510, and 765 mg/m2) or dose cumulativeandpatients at 230 and 345 mg/m2). It was dose related and mg/m2â€¢â€¢¿PATIENT46 -100 was not observed at dose levels below 85 mg/m2. Clinical man mg/m2^1 PATIENT 21 - 55 ifestations were highly variable and consisted of erythema and swell ingpatients),followed, of hands and feet, sometimes with bullous lesions (4 4Â¡ E t 3 iâ€”r patientstreatedwith further courses, by dry desquamation. In 5 subcutaneousedemawith the highest cumulative doses, diffuse kg.Theywas also observed, with weight gain ranging from 2 to 15 Ã¬\100.00: byproteinuria,all had normal renal, hepatic, and cardiac functions, assessed *^| 1 creatinine clearance, liver function tests, and left ventric â€¢¿1000::0.0:â€¢¿: \S" ^*-> â€”¿ ularrapidlyresponsive ejection fraction. Edema and weight gain were highly and usuallyoccurredto diuretic (furosemide) therapy. The first signs infusion,andin the second week following the first or second patientshadoften, partial recovery was observed within 15 days. Four consistentwithcutaneous biopsies, and histological examination was scleroderma-likepatternsnonspecific toxidermic cutaneous reaction or 4.0 8.0 12.026.0TimÂ« 160 20.0 240 (antihista-mininics,in 2 patients (data not shown). Various treatments butshowed anti-Hi and anti-H2. corticosteroids) were attempted (hours)Fig. 1. Representative plasma concentration-time curves from two patients who re little efficacy in improving or preventing cutaneous toxicity. ceived 55 or 100 mg/m2. Curves are the lit of the data to two- or three-compartment Nail changes, with brown discoloration, onycholysis, and growth ar-WHOmodels, respectively. 1039

Table 5 Mean (SD) pharmacokineÃ±c parameters urinary Dose level of patients excretion (mg/m2)203040557085100115No.(no. ofcourses)1(1)2(3)1 duration(h)11.58(0.80)11.68(0.75)1.37(0.53)1.61(0.81)2.03(0.09)1.84(0.28)Peakconcentration(ug/ml)0.820.64(0.45)0.420.82(0.38)1.91(0.32)2.42(0.92)2.41(0.35)2.68(0.93)M"(h)2.24.6(2.8)3.82.0'2.5(1.4)13.6'(6.1)18.5Â«(10.7)9.6(5.8)AUC(ug-h/ml)0.961.26(0.34)0.671.42'2.79(0.85)4.10'(0.92)5.93(1/h/m2)20.824.9(6.3)59.739.9'26.7(8.2)22.6'(7.7)17.0*(1.6)22.2(0.7)VÂ«(1/m2)16\2Câ€”15C16(6)72'(24)95Â«(62)53(39)24-h(%dose)9d1.22.7'2.3'2.1(.2)3.5(2.5)2.8"(1.3)

(1)3(3)2(3)6(6)4(4)4(4)Infusion

"(0.53)5.19(0.16)CL"

"Terminal half-life, two-compartment model up to 70 mg/m", three-compartment model thereafter. * Total plasma clearance. ' n = 1. d â€”¿.nodata. 'n = 2. 'n = 4.

observation of the terminal elimination phase at the lower doses, as Antitumoral Activity. Four patients (one with ovarian adenocar- illustrated in Fig. 1. At doses of 85 mg/m2 and higher, the elimination cinoma, one with small cell lung cancer, one with breast cancer, and profile was clearly triphasic, with a rapid initial half-life of about 5 one with unknown primary carcinoma) achieved partial response (Ta min, an intermediate phase of 1 h half-life, and a terminal phase, ble 6). Eight patients (5 with ovarian cancer and 3 with breast cancer) ranging from 10 to 18 h [overall mean, 13.5 Â±(SD) 7.5 h]. Plasma without measurable lesions had a clear subjective improvement, with clearance averaged 21.1 Â±5.3 liter/h/m2. The apparent terminal half- a significant decrease (>50%) in tumor markers lasting for more than life (2.0-4.6 h) estimated at lower doses resulted from a mix between 3 months. All have received I-5 prior chemotherapy regimens. the intermediate and terminal phases. Since Vss estimate is very sen sitive to terminal half-life, Vss also appeared to be dose dependent. The most relevant values were obtained at the higher doses (53-95 DISCUSSION liter/m2; overall mean, 72 Â±40 liter/m2). Urinary excretion of Tax- According to the classical definition, the maximum tolerated dose otere was low (2-3% of the dose over 24 h). A significant relationship of Taxotere given as a single l-2-h infusion every 3 weeks should be was observed between AUC and change (percentage decrease) in between 70 and 85 mg/m2, based on a 50% incidence of noncumu neutrophil count (observed during the same course), using a sigmoid lative and dose-dependent neutropenia. However, it was of short du Â£maxmodel (r = 0.672, P = 0.001), as illustrated in Fig. 2. ration and was rarely complicated by fever. As a matter of fact patients The AUC50 was 0.967 ug X h/ml (SD of estimation: 24.7%), with could tolerate 115 mg/m2 (a dose which induces >80% grade IV k estimated at 1.36 (SD of estimation: 30.2%). neutropenia). At all dose levels neutropenia was reversible in 3 weeks The patients who experienced cutaneous toxicity had similar sys in all but one patient. Neutropenia was also the dose-limiting toxicity temic exposure (AUC) and peak plasma levels, assessed at the first with Taxol (5-11), the maximal tolerated dose of which ranged be course, than those who did not. Yet the number of assessable patients tween 190 and 275 mg/m2. Thrombocytopenia was rare (11% of is too low to draw a firm conclusion (data not shown). patients), and anemia was more frequently observed (56% of patients), but this was due not only to Taxotere treatment. As previously ob 100 -i served with vinorelbine (28), Taxol (19), or topotecan (29), this he- matological side effect was not the only one used to recommend a dose for phase II studies. Rather, it was the association of neutropenia, mild paresthesia, and cutaneous side effects (which led to treatment discontinuation in four patients) that allow for the recommendation of 100 mg/m2 as a dose for phase II studies. Unlike Taxol, Taxotere did not induce significant acute hypersen- sitivity reactions. Up to 10% of patients receiving Taxol, although also receiving antianaphylactic preventive treatment, still experience se vere reactions, such as hypotension and dyspnea, leading to a discon tinuation of treatment (30). In our study, 7 patients experienced tran sient rash and/or pruritus, several hours after the end of the infusion of Taxotere. Alternatively, cutaneous toxicity, not observed with Taxol (apart from allergic reactions like erythema), was observed in 18 patients (28%). It was dose related and cumulative and was observed only beyond 70 mg/m2. The very first manifestations occurred during the first week after Taxotere infusion and consisted of aerai syndrome, AUC(Mg.h/ml) with dry erythema of palms and soles or bullous lesions. With further Fig. 2. Percentage change in neutrophils versus Taxotere AUC curve; fit of the data to administration, swelling and edema of limbs were more prominent. i sigmoid Â£maxmodel. All of these signs disappeared after treatment discontinuation. The 1040

Table 6 Characteristics of the responding patients Previous chemotherapy Response (months)

TumortypeOvary (mg/m)285 regimensDDP"2 VAI~+ ofdiseasePeritoneum + BreastSCLCUnknown 11585115Prior 32 LiverBronchusLiverOnset2 222Duration6 3+5+2+ +3 ++ primaryDose +DOX +Site ' DDP, cu-platinum; DOX, doxorubicin; VA. Vinca alkaloids (vindesine or vinorelbine); SCLC. small cell lung cancer.

mechanisms remain unclear, and biopsies did not show any specific Interestingly. 4 patients with ovarian, small cell lung or breast, and pathologic change. Some of these signs and nail changes were remi unknown primary cancer achieved a partial response, and 8 patients (5 niscent of cutaneous toxicity (aerai erythema) induced by bleomycin, with ovarian cancer, 3 with breast cancer) had a minor response high-dose cytarabine, and, to some extent, fluorouracil (31-33). The lasting more than 3 months (range, 4-8+ months). role of polysorbate 80 and ethanol in this peculiar toxicity is unclear. The results of this trial suggest that Taxotere can be safely admin Grade 1-2 limb paresthesias occurred in 11 patients (17%) and was istered to patients, with neutropenia being the main limiting loxicity. not prominent. As with Taxol (34-35). this neurotoxicity was dose The recommended dose for phase II trials, with this schedule, is 100 dependent (5 patients at the maximal tolerated dose) and might be mg/m2 every 3 weeks, given as a 1-h i.v. infusion (with the formula cumulative (5 patients after the third course). tion in polysorbate). Cumulative cutaneous toxicity deserves further Unlike Taxol, Taxotere infusion did not induce bradycardia. In fact, investigations and might lead to further dose reduction. asymptomatic bradycardia occurred in up to 29% of patients treated with Taxol (12) at doses over 170 mg/m2. More severe cardiac dis ACKNOWLEDGMENTS turbances were observed in 5% of patients but are poorly attributable to Taxol (12). Alopecia was dose dependent and was first observed in The authors gratefully acknowledge the expert secretarial assistance of patients treated with a dose of 55 mg/m2 of Taxotere. Other toxicities, Patricia Bertrand and data management of Dalila Oulid Aissa. such as gastrointestinal, mucosal, liver, and renal toxicities, were uncommon and, most of the time, mild. These differences in toxicities REFERENCES between Taxol (anaphylactoid reactions, cardiac disturbances) and 1. Wani, M. C. Taylor, H. L., Wall. M. E., Coggon. P., and McPhail, A. T. Plant Taxotere (cutaneous reactions) may be explained by specific proper antitumor agents. VI. The isolation and structure of taxol. a novel antileukemic and ties of the molecules and/or, alternatively, by different excipients used antitumor agent from Taxus hrevifnlia. ÃŒ.Am.Chem. Soc.. 9-J: 2325-2327. 1971. 2. Schiff. P. B.. Fani. Â¡..and Horwilz, S. B.. Promotion of microtubule assembly in viiro in their formulation. by laxol. Nature (Lond.). 277; 665-667. 1979. The pharmacokinetics of Taxotere was determined using a rapid 3. Kumar. N. Taxol-induced polymerization of purified tubulin. 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Jean-Marc Extra, Frédérique Rousseau, René Bruno, et al.

Cancer Res 1993;53:1037-1042.

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