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(CANCER RESEARCH 46, 4827-4830, September 1986]
Phase I and Pharmacological Continuous Infusion1
Study of Vinblastine by Prolonged
Mark J. Ratain2 and Nicholas J. Vogelzang Joint Section of Hemalology I Oncology, University of Chicago Pritzker School of Medicine, and Michael Reese Medical Center, Chicago, Illinois 60616
maximally tolerated dose of CVI3, and to prospectively corre
ABSTRACT Vinblastine is an antimitotic plant alkaloid with an elimination halflife of about 24 h. The cytotoxicity of vinblastine against solid tumor cell lines in vitro is markedly increased with prolonged exposure. Therefore, 24 patients with advanced malignancy were treated with a prolonged continuous i.v. infusion of vinblastine given via an impiantatilo pump. The patients received vinblastine for a median of 12 wk (range, 2 to 36 wk), at dosages ranging from 0.5 to 0.9 mg/m2/day. The steady-state serum vinblastine concentration (VLBâ€ž)was determined at 2- to 3-wk intervals in each patient for correlation with toxicity. The dose-limiting toxicity was leukopenia in nine patients and peripheral neuropathy in one patient. Thirteen patients developed progressive disease prior to reaching doselimiting toxicity, and one patient withdrew from the study because of severe local toxicity at the injection site. There was only mild toxicity at infusion rates <0.6S mg/m2/day, but at no dosage did reproducible toxicity occur. The maximum VLBâ€žwas significantly higher in those patients with severe leukopenia than nontoxic patients (1.91 versus 1.00 ng/ml; P = 0.001), but there was no significant difference in the maximum dosage between the two groups (0.76 versus 0.74 mg/m2/day). Our results dem onstrate that prolonged infusions of vinblastine are feasible, achieving V'l.H.s >1 ng/ml, a drug concentration which is cytotoxic in vitro. The recommended starting dose of vinblastine for Phase II studies is 0.7 mg/ m2/day, with dosage adjustments every 2 to 4 wk based on the white blood cell count and VLBÂ».Prospective monitoring of VLB.., with dosage adjustment to maintain VLBâ€ž<1.S to 2.0 ng/ml, may avoid the unex pected occurrence of severe myelosuppression.
INTRODUCTION Vinblastine is an antimitotic plant alkaloid that has been in clinical use for over 20 yr ( 1). The drug is a potent antineoplastic agent with cytotoxic activity in vitro at concentrations of 1 ng/ ml or greater (2). However, the cytotoxicity of vinblastine in vitro is very dependent on the duration of exposure (2), possibly due to the rapid efflux of vinblastine from cells when the extracellular drug is removed or eliminated (3, 4). Following conventional i.v. bolus therapy, serum vinblastine levels are in the "cytotoxic range" for about 48 to 72 h (5). Continuous infusion of vinblastine may therefore provide a more pronounced cytotoxic effect. Five-day vinblastine infu sions were first utilized by Yap et al. (6) with an apparent improvement in therapeutic index. These investigators treated 30 patients with advanced refractory breast cancer and obtained a 40% response rate with tolerable myelosuppression at doses of 1.4 to 1.8mg/m2/day. The development of reliable drug administration pumps and long-term venous access catheters has made prolonged infusion of vinblastine and other drugs clinically feasible (7). In this study, we have used a new totally impiantatile battery-powered drug delivery system in order to achieve a reliable and stable vinblastine infusion rate over a prolonged period of time (8). The objectives of this study were to define the toxicity and Received 9/23/85; revised 5/30/86; accepted 6/3/86. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. ' This work was supported in part by Medtronic, Inc., the Jazz and Blues Fund, and USPHS Grant 5M01-RR00055. 2 To whom requests for reprints should be addressed.
late the VLBM with toxicity. This report demonstrates that a VLBM greater than 1 ng/ml can be safely achieved and main tained for several months with acceptable clinical toxicity. In addition, we have shown that the development of severe leu kopenia is highly correlated with an elevated VLB^. MATERIALS AND METHODS Patients. The 24 patients entered in this study (Table 1) met the following eligibility criteria: histolÃ³gica! proof of malignant disease refractory to standard therapy or for which no standard therapy exists; recovery from prior myelosuppressive therapy; a minimum life expect ancy of 8 wk; acceptable bone marrow reserve (WBC >3000 cells/Ml and platelet count >75,000 cells/Ml); acceptable hepatic and renal function (bilirubin and creatinine <2.0 mg/dl); ability to tolerate a surgical procedure for placement of the pump; no central nervous system involvement; and no cardiac pacemaker. Written informed consent was obtained in accordance with federal and institutional guidelines. Treatment Design. All patients were admitted to the University of Chicago Clinical Research Center for initiation of therapy. The pump (Drug Administration Device System Model 8600 or 8610; Medtronic Corp., Minneapolis, MN) was surgically placed under local anesthesia unless the patient had been implanted with a pump previously (8). Vinblastine (Lilly Corp., Indianapolis, IN) was shown to be stable in the pump at 37Â°Cwith less than 2% decay over 2 wk and less than 7% decay over 4 wk.4 A small i.v. bolus dose (3 mg/m2) of vinblastine was administered, and blood samples were collected at specified times for determination of vinblastine pharmacokinetics in each patient.5 Vinblastine was dissolved in 20 ml of 0.9% sodium chloride solution for use in the pump. The pump reservoir was filled, and the pump was started 72 h after administration of the bolus dose. The starting dosage for CVI was 0.5 mg/m2/day in 13 patients, 0.6 mg/m2/day in 10 patients, and 0.7 mg/m2/day in one patient. The latter patients were begun at a higher starting dose because of minimal toxicity with earlier patients at the first two dose levels. Due to device limitations, the precise calculated dose could not always be administered, so that a dose of 0.5 mg/m2/day represented a range from 0.45 to 0.54 mg/m2/day (8). Patients returned at 2- to 3-wk intervals for assessment of toxicity (physical examination, complete blood count, chemistry profile) and refilling of the pump. At each visit, blood was obtained for determina tion of VLBâ€ž.The infusion rate was escalated by approximately 0.1 mg/m2/day each visit, if the WBC was >3000//il and if there was tolerable (sCALGB Grade 1) nonhematological toxicity. The infusion rate was decreased by 0.1 mg/m2/day if Grade 3 toxicity occurred. If Grade 4 toxicity occurred, the infusion was discontinued and restarted at a reduced dose (by 0.1 mg/m2/day) only when there was < Grade 1 toxicity. The infusion was continued at the maximally tolerated rate to maintain a WBC of 2000 to 3000/iil with < CALGB Grade 1 nonhe matological toxicity. Treatment was stopped when there was definite evidence of progressive disease. Therapeutic effects were evaluated with standard criteria. Minor response was defined as a reduction of less than 50% but more than 3 The abbreviations used are: CVI, continuous vinblastine infusion; VLBÂ«, steady-state serum vinblastine concentration; CALGB, Cancer and Leukemia Group B; NSB, nonspecific binding; Air. area under the curve. 4 D. Ellsberry (Medtronic Corp., Minneapolis, MN), personal communication. 5 M. J. Ratain, N. J. Vogelzang, and J. A. Sinkule. Interpatient and intrapatient variability in vinblastine pharmacokinetics, submitted for publication.
25% in the sum of the products of the longest perpendicular diameters of all measurable lesions and no appearance of new lesions or enlarge ment of existing lesions. Stable disease was defined as an increase of less than 25% or a reduction of less than 25% in the measured tumor and no appearance of new lesions. Progressive disease was defined as an increase of 25% or more in the measured tumors or the development of new lesions. Vinblastine Radioimmunoassay. The VLBÂ»was determined by radioimmunoassay, using a modification of the method of Sethi et al. (9). The antiserum was raised as previously described (10) and generously provided in the lyophilized form by Dr. Mary Root, Lilly Research Laboratories, Indianapolis, IN. Antiserum Lot 24-245-6-R was used for all determinations. [3H]Vinblastine was purchased from Amersham Corp., Arlington Heights, IL. The radioimmunoassay was performed as previously described (9). However, only 150 to 200 pg of [3H]vinblastine were used to improve the sensitivity of the assay to 0.1 to 0.2 ng/ml. The antibody concen tration was adjusted to provide 40 to 50% binding of the [3H]vinblastine in the absence of unlabeled vinblastine. As the NSB of [3H]vinblastine in a patient's serum was increased up to 150% (compared to buffer), a NSB control was added for each patient sample. The bound counts in the NSB control were subtracted from the bound counts in the presence of antibody. There was no difference between serum and plasma NSB, but there was marked inter- and intrapatient variability in the NSB. The NSB was decreased by dilution of the serum, and samples were diluted before analysis when possible. All samples were analyzed in duplicate, and a standard curve from 0.1 to 3.2 ng/ml was run simul taneously. The assay was reproducible to Â±10%. Statistical Analysis. All statistical testing was performed on a Profes sional 350 system (Digital Equipment Corp., Waltham, MA), using the RS/1 software package (Bolt, Beranek, and Newman, Cambridge, MA).
(adenocarcinoma)UreteralOvarianAdenoid cysticHodgkin's diseaseMelanomaAdenocarcinoma of unknown origin245814:1032131349422
DISCUSSION As the cytotoxicity of vinblastine in vitro is highly schedule dependent (2, 13), it is important to consider alternative treat ment schedules to standard bolus administration. Previous in vestigators have utilized 5-day vinblastine infusions (6, 14, 15). In this study, we demonstrate that prolonged CVI (for up to 36 wk) is also feasible. The dose-limiting toxicity of CVI is leukopenia, which was reversible upon dosage reduction or discontinuation of the infusion. Although there was only one episode of severe leu kopenia (Grade >3) at the first two dose levels and a 40% incidence at the highest dose level, there was no dose level at which reproducible toxicity occurred. In addition, there was no difference between the maximal infusion rate or cumulative 4828
Table 2 Summary of outcome of continuous infusion vinblastine in 24 patients The starting and maximum doses, maximum VLBM,cumulative vinblastine dose, and infusion duration (at the time of minimum WBC) are shown for each patient. In only 9 patients did the WBC decrease to less than 2000/^1, necessitating dose reduction or temporary discontinuance of the infusion. The maximum VLBâ€žis omitted for 3 patients due to incomplete collection of serum VLBâ€žsamples. Six patients remain on study.
vinblastine to to mini minimum time mum vinblastine VLBÂ« WBC WBC dose dose on study WBC on study (mg/m2/day)0.730.800.540.940.510.900.860.800.490.740.490.830.660.600.840.820.850.910.780.930.690.800.780.70Maximum (mg/m2)49511154227257741413312322028533192954863 (mg/m2)8115611542210663240+141331 (X 1000//J)2.01.83.94.184.108.40.206.95.81.08.61.40.711.53.812.39.47.06.61.21.08.45.83.2Time (ng/ml)0.582.000.480.901.501.051.450.972.500.962.100.7220.127.116.11.830.702.402.400.862.40Minimum (wk)81221051412153153646126181810116983Total Patient123456789101112131415161718192021222324Starting (mg/mVday)0.520.530.540.500.510.570.500.530.490.500.500.610.610.600.510.520.490.550.580.590.620.570.590.70Maximum (wk)24272105221336+3IS323+4712618+18+1013+1111
Table 3 Toxicity of continuous infusion vinblastine The toxicity for all 24 patients by dose is shown below. The doses are rounded to the nearest 0.1 mg/m2/day. Most patients were treated at multiple dose levels, usually at 0.1 -mg/m2/day increments. However, two patients were escalated from 0.5 to 0.7 mg/m2/day, and one patient was escalated from 0.6 to 0.8 mg/m2/day.
No. of toxic patients by
gradeDose (mg/m2/day) patient-wk0.5
No. of patients/
13/360.6 2 3-412
0.5OnO 1â€¢\j â€”
0(0) 3-4123-4I 2(40)1(4)
24/285CALGBgrade1 1(4) 0(0) 9(38)Peripheral1(4) " Numbers in parentheses, percentage of patients at dose level.
dose administered to the toxic (Grade >3) versus nontoxic patients. On the other hand, toxic patients had a mean maxi mum VLBSSapproximately double that of the nontoxic patients. This dissociation between dose and VLBSSindicates significant interpatient differences in vinblastine pharmacokinetics as pre viously reported by other investigators, possibly due to interpatient differences in hepatic and renal function (5, 14). The only prior study of CVI is by Lokich et al. (16) who also found myelosuppression to be dose limiting at infusion rates >
Fig. 1. Comparison of nontoxic and toxic patients by maximum VLBâ€žand dose. Patients designated Not Toxic always had WBC >2000/pl; patients desig nated Toxic had at least one clinic visit with WBC <2000/Â«J.The horizontal lines represent the mean maximum VLBâ€ž(A) or infusion dose (B) for each subgroup of patients.
0.75 mg/m2/day. Most of those 26 patients received a dosage of only 0.5 mg/m2/day, with 4 patients treated at higher infu sion rates. Responses occurred in patients with malignant mel anoma and soft tissue sarcoma, but they were of short duration (less than 6 wk).
Peripheral neuropathy was the only significant nonhematological toxicity in our study but was dose limiting in only one patient. However, as the median duration of treatment was only 12 wk, we cannot exclude the possibility that there may be significant cumulative neurotoxicity with higher total doses as is commonly seen with the Vinca alkaloids (17). Since this was a Phase I study, it cannot address the efficacy of CVI. Although no major responses occurred in this study, 5day vinblastine infusions have significant activity in refractory breast cancer (6) and a variety of other malignancies (18). There are theoretical reasons to pursue this vinblastine schedule, as drug concentrations that are cytotoxic in vitro (>1 ng/ml) (2) can be maintained for up to 36 wk. In addition, both the total vinblastine dose and AUC of serum vinblastine (per mo) are increased in comparison to the 5-day infusion schedule. Using a 5-day infusion schedule, it is possible to deliver 7.5 to 10.0 mg/m2/30-day cycle with an AUC of 229 ng h/ml (derived from data in Ref. 14). With prolonged CVI, one can deliver 21 mg/m2/30 days (at 0.7 mg/m2/day) with an AUC of 1008 ng h/ml (assuming a VLBM of 1.4 ng/ml). We recommend an initial infusion rate of 0.7 mg/m2/day for future clinical trials of CVI. The infusion rate can be slowly increased (every 2 to 4 wk), using both the WBC and VLBS5as guides to the maximum dose tolerated without severe myelosuppression. The use of prospective monitoring of VLBSSto avoid a prolonged VLBH >1.5 to 2.0 ng/ml may allow the prevention of severe myelosuppression. This hypothesis should be tested in future Phase II trials. ACKNOWLEDGMENTS We appreciate the assistance of the following individuals: Dr. John Holt for laboratory space and assistance with the radioimmunoassay; Dr. Dennis Ellsberry for performing the stability studies; Dr. Mary Root for providing the vinblastine antiserum; Dr. Harvey Golomb for his support; Dr. Richard Schilsky and Dr. Joseph Sinkule for many helpful suggestions; John O'Connell for technical assistance; Maureen Ruane and Kathy O'Laughlin for their nursing expertise; and Margaret Serelis and Dora Currin for preparation of the manuscript. We are also indebted to the entire staff of the University of Chicago Clinical
Research Center, without whom this study would not have been possi ble.
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Phase I and Pharmacological Study of Vinblastine by Prolonged Continuous Infusion Mark J. Ratain and Nicholas J. Vogelzang Cancer Res 1986;46:4827-4830.
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