A Phase I study of infusional vinblastine in combination with the p-glycoprotein antagonist PSC 833 (valspodar)

A Phase I Study of Infusional Vinblastine inCombination with the P-Glycoprotein Antagonist PSC833 (Valspodar)

Susan Bates, M.D.1

Min Kang, Pharm.D.1

Beverly Meadows, M.S.1

Susan Bakke, R.N.1

Peter Choyke, M.D.2

Maria Merino, M.D.3

Barry Goldspiel, Pharm.D.4

Isagani Chico, M.D.1

Tom Smith, Ph.D.5

Clara Chen, M.D.6

Robert Robey, B.Ch.E.1

Raymond Bergan, M.D.7

William D. Figg, Pharm.D.1

Tito Fojo, M.D., Ph.D.1

1 Cancer Therapeutics Branch, Center for CancerResearch, National Cancer Institute, National Insti-tutes of Health, Bethesda, Maryland.

2 Department of Radiology, Clinical Center, Na-tional Institutes of Health, Bethesda, Maryland.

3 Department of Pathology, Center for Cancer Re-search, National Cancer Institute, National Insti-tutes of Health, Bethesda, Maryland.

4 Clinical Center Pharmacy, National Institutes ofHealth, Bethesda, Maryland.

5 Novartis Pharmaceuticals Corporation, EastHanover, New Jersey.

6 Nuclear Medicine Department, National Institutesof Health, Bethesda, Maryland.

7 Department of Medicine, Northwestern UniversityMedical School, Chicago, Illinois.

Address for reprints: Susan Bates, M.D., CancerTherapeutics Branch, National Cancer Institute,National Institutes of Health, 9000 Rockville Pike,Building 10, Room 12N226, Bethesda, MD 20892;Fax: (301) 402-0172: E-mail: [email protected]

Received September 7, 2000; revision receivedApril 4, 2001; accepted April 12, 2001.

BACKGROUND. PSC 833 is a second-generation P-glycoprotein (Pgp) antagonist

developed to reverse multidrug resistance (MDR). The authors conducted a Phase

I study of orally administered PSC 833 in combination with vinblastine adminis-

tered as a 5-day continuous infusion.

METHODS. Seventy-nine patients with advanced malignant disease were enrolled in

the trial and treated with escalating doses of PSC 833. Pharmacokinetic interac-

tions between PSC 833 and vinblastine were anticipated. Accordingly, when dose

limiting toxicities were observed, the dose of vinblastine was reduced as PSC 833

was escalated. Three schedules and two formulations of PSC 833 were used in the

study.

RESULTS. The maximum tolerated doses of PSC 833 were 12.5 mg/kg orally every

12 hours for 8 days for the liquid formulation in combination with 0.9 mg/m2 per

day vinblastine as a continuous intravenous infusion (CIV) for 5 days; and 4 mg/kg

orally every 6 hours for 8 days for the microemulsion formulation in combination

with 0.6 mg/m2 per day vinblastine CIV for 5 days. The principal toxicities for PSC

833 were ataxia and paresthesias and for the combination, constipation, fever. and

neutropenia. Increased oral bioavailability and increased peak and trough concen-

trations were observed with the microemulsion formulation. Significant interpa-

tient variability in pharmacokinetic parameters was observed. Ten patients studied

at the MTD for PSC 833 (4 mg/kg orally every 6 hours for 8 days) had inhibition of

rhodamine efflux from CD56 positive peripheral lymphocytes as a surrogate for

Pgp antagonism. Among 43 evaluable patients with clear cell carcinoma of the

kidney, 3 patients had complete responses, and 1 patient had a partial response.

CONCLUSIONS. PSC 833 in combination with vinblastine can be administered safely

to patients provided the vinblastine dose is adjusted for pharmacokinetic interac-

tions. The high interpatient variability is a significant confounding factor. Surro-

gate studies with CD56 positive cells suggest that Pgp inhibition in the clinical

setting is achievable. Improved methods for predicting pharmacokinetic interac-

tions should improve future studies. Cancer 2001;92:1577–90.

© 2001 American Cancer Society.

KEYWORDS: renal cell carcinoma, P-glycoprotein antagonist, drug resistance rever-sal, pharmacokinetic interaction.

I t is well recognized that cells can reduce intracellular drug concen-trations by energy dependent transport mechanisms and that this

can confer resistance to chemotherapy. The best understood mech-anism is that mediated by the drug transporter, P-glycoprotein (Pgp),encoded by the multidrug resistance (MDR) gene, MDR-1. Although ithas been studied intensively in the laboratory, Pgp became of clinicalinterest when it was discovered that resistance reversal could be

1577

© 2001 American Cancer Society

achieved by the addition of other substrates, whethercompetitive or noncompetitive. However, verapamiland other first-generation reversal agents had limitedsuccess in the clinic, presumably due to inability toachieve serum concentrations sufficient to reversedrug resistance. Second-generation agents have beendeveloped, promising greater potency and lesser tox-icity.1

PSC 833, the most widely tested second-generationagent, is a cyclosporine-D derivative that is nonneph-rotoxic and nonimmunosuppressive.2 The Phase Istudy described herein was started to determine thedose limiting toxicity (DLT) of PSC 833 and to ascer-tain the dose of vinblastine that could be administeredin combination with PSC 833. Vinblastine was chosenas the antineoplastic agent based on extensive in vitrodata indicating that it is susceptible to Pgp-mediatedresistance. An infusional schedule was selected, be-cause prior studies had shown that continuous expo-sure could reduce the relative resistance of tumor cellswith high levels of Pgp overexpression.3 In addition,the 5-day infusional schedule for vinblastine had beenreported to show modest efficacy in patients withrenal cell carcinoma and breast carcinoma.4 – 6

Several lessons were learned from first-generationstudies with Pgp antagonists, including recognitionthat the antagonists frequently reduced the clearanceof anticancer drugs.7 Among the first-generationagents, this reduction in clearance was reported mostfrequently with cyclosporine A. Along with inhibitingPgp-mediated transport, cyclosporine A is known toinhibit the metabolism of compounds that are sub-strates for the 3A4 isoenzyme of cytochrome P450.8,9

Numerous anticancer agents, including the Pgp sub-strates doxorubicin, etoposide, and paclitaxel, are sub-strates for this isoform. Consequently, cyclosporin Acan impact on the clearance of these agents by inhib-iting either Pgp or the 3A4 isoenzyme of cytochromeP450, and the relative contribution of each has notbeen delineated. The knockout model of the murineMDR-1 orthologues has demonstrated a $ 2-fold in-crease in serum and tissue concentrations of vinblas-tine, digoxin, and paclitaxel.10 –13 In addition, becausePgp is an essential part of the blood-brain barrier,marked increases in central nervous system concen-trations of these agents are observed in the mdr1a/b(2/2) mouse.14 These studies suggest that inhibitionof Pgp alone can account for some of the pharmaco-kinetic interactions observed with the addition ofmodulators.

We performed a Phase I study of the combinationof PSC 833 plus vinblastine, seeking the maximumtolerated dose (MTD) for PSC 833 and lowering thedose of vinblastine as needed to determine the MTD

of vinblastine in combination with PSC 833. Ataxiawas the DLT for PSC 833, whereas vinblastine toxici-ties, including febrile neutropenia and constipation,required a reduction in vinblastine dose. During thecourse of this study, two PSC 833 formulations andthree separate dosing schedules were studied. A sep-arate MTD was established for each dosing schedule;all required a significant reduction in vinblastine doseto avoid toxicity.

MATERIALS AND METHODSPatient SelectionSeventy-nine patients were enrolled on the trial: In-formed consent was obtained from all patients. En-rollment criteria included age . 18 years, a Karnofskyperformance status $ 70%, and a life expectancy of. 3 months. Patients were ineligible if they had re-ceived chemotherapy, immunotherapy, or radiationtherapy in the 4 weeks prior to study entry. Patientswere required to have normal hepatic function (ala-nine and aspartate aminotransferase levels # twicethe upper limit of normal), normal renal function (cre-atinine clearance $ 75 mL per minute), and normalhematologic parameters (white blood cell count$ 4000, absolute neutrophil count $ 2000, and plate-let count $ 100,000). During the study, patients couldnot be treated simultaneously with PSC 833, otherP450-interactive compounds, or other drugs known tointeract with cyclosporine A. The 79 patients who wereenrolled included 2 patients who did not meet alleligibility criteria but were admitted on a compassion-ate basis; these patients were included in the toxicityanalysis. One additional patient who had a rapid andsevere reaction to the infusional vinblastine never re-ceived PSC 833 and was considered not evaluable fortoxicity or response. Thus, 78 patients were includedin the toxicity analysis.

Treatment SchemaPSC 833 was supplied by Novartis PharmaceuticalsCorporation (East Hanover, NJ) and distributedthrough Clinical Therapy Evaluation Program (CTEP)/National Cancer Institute (NCI) in two different for-mulations: 1) a liquid formulation in which PSC 833was resuspended at 100 mg/mL in a mixture of etha-nol, corn oil, and maize oil (labrifil) that was admin-istered every 12 hours and was used in the first 44patients; and 2) a formulation in which PSC-833 wassuspended as a microemulsion in gel capsules con-taining D-L-a tocopherol, propylene glycol, absoluteethanol, maize oil (labrifil), and Cremophor RH 40 thatwas used in the other 34 patients. The microemulsionwas administered at intervals of 8 hours or 6 hours.The protocol design called for a starting dose of vin-

1578 CANCER September 15, 2001 / Volume 92 / Number 6

blastine of 1.2 mg/m2 per day and escalation of thedose of PSC 833. A vinblastine dose of 1.2 mg/m2 perday was chosen, because, in a previous study of infu-sional vinblastine in combination with cyclosporine A,DLTs due to reduced vinblastine clearance requiredreduction of the vinblastine dose from 2 mg/m2 perday to 1.2 mg/m2 per day for the 4-day infusion.15,16

For a further precaution, in the first combined cycle,the initial cohort of patients received vinblastine 1.2mg/m2 per day for 3 days, and this was increased to 4days and then to 5 days in subsequent cohorts.

Patients were treated according to the schemaoutlined in Figure 1A. The study was designed so thatpatients received vinblastine and PSC 833 separatelyin the first cycle and together in Cycle 2 and beyond.This design was chosen to allow the pharmacokineticsof each agent to be determined separately and in thecombination. In the first cycle, the 5-day vinblastineinfusion was started on Day 1, and the 8-day PSC 833administration was started on Day 8. In Cycle 2, oralPSC 833 was started 72 hours before the initiation ofthe vinblastine infusion. After Cycle 2, patients weretreated at 4-week intervals provided that recovery ofbone marrow function had occurred and that nonhe-matologic toxicities had resolved. When toxicity wasnot defined by the NCI Common Toxicity Criteria, aseparate scale was adopted. This is shown in Figure

1B. The DLT of a given vinblastine/PSC 833 dose wasdefined as either Grade 3 or Grade 4 nonhematologictoxicity (excluding hyperbilirubinemia), fever withneutropenia, or an absolute neutrophil count , 500for . 4 days. However, even if DLT was encountered,further dose escalations of PSC 833 were allowed pro-vided the vinblastine dose was reduced. One of theDLTs observed was constipation. This complicationwas ameliorated in part by the use of a prophylacticregimen consisting of docusate sodium (200 mg twiceper day), senna fruit tablets (two tablets twice perday), and milk of magnesia (30 mL at bedtime). Pa-tients were instructed to increase their oral fluid in-take with this regimen. The first reduction was to avinblastine dose of 0.9 mg/m2 per day by continuousintravenous infusion (CIV) for 5 days (75% of the start-ing dose). When at least two patients on a given doselevel of PSC 833 required reduction of the vinblastinedose to 0.9 mg/m2 per day CIV for 5 days, all patientson subsequent dose levels received the lower dose ofvinblastine as the PSC 833 dose escalation progressed.The escalation of PSC 833 dose continued until at leasttwo patients required a reduction in the vinblastinedose to 0.6 mg/m2 per day CIV for 5 days (50% of thestarting dose). The MTD for the combination was de-fined as the dose at which fewer than two of six pa-tients had DLT. Patients were continued on the studyuntil disease progression was documented, unless itwas considered in the patient’s best interest to beremoved from the study. On completion of the study,tumor dimensions were measured by a radiologist(P.C.) from radiographic studies of patients who wereconsidered to have stable disease or a response. Re-sponses were evaluated by taking bidimensional mea-surements of lesions; when numerous lesions werepresent, measurements of four to six index lesionswere obtained.

Pharmacokinetic Sampling and AnalysisSampling for PSC 833 pharmacokinetics was per-formed during the first cycle when PSC 833 was ad-ministered alone and during the second cycle whenvinblastine was administered simultaneously. Sam-ples (7 mL) were drawn immediately prior to the doseon Day 1 (prelevel) and then at 0.5 hours, 1 hour, 2hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, and12 hours after the dose. Sampling obtained in the first10 patients was used to characterize the pharmacoki-netics and bioavailability of the PSC 833 liquid formu-lation versus the intravenous infusion.17 Pharmacoki-netic parameters were calculated by weighted,nonlinear, least-square analysis fitting a one-compart-ment and two-compartment, open, linear model withand without a lag in absorption using the ADAPT II

FIGURE 1. (A) Treatment schema showing the drug administration schedules

for Cycles 1 and 2. (B) Definitions of toxicity grading scale for paresthesias and

gait disturbance due to the administration of PSC 833, a second-generation

P-glycoprotein antagonist. CIV: continuous intravenous infusion; CTC: National

Cancer Institute Common Toxicity Criteria.

Infusional Vinblastine with PSC 833/Bates et al. 1579

software program (Biomedical Simulations Resource,University of Southern California, Los Angeles, CA).Model selection was determined based on the Akaikeinformation criterion and visual examination of thedifference between the measured and fitted concen-trations. In the current pharmacokinetic analysis, out-lier points ($ 2 standard deviations outside the fittedline) were not disregarded, and all data points wereincluded in the fitting of the data. The regressioncoefficient (r2) values reported are the actual valuesand not the skewed values. A two-compartment modelincorporating a lag time to account for delays in oralabsorption was used for this analysis.

PSC 833 RadioimmunoassayPSC 833 concentrations in whole blood samples weredetermined by the Bioanalytics and PharmacokineticsSection, Drug Metabolism and Pharmacokinetics De-partment at Novartis Pharmaceuticals Corporation(East Hanover, NJ). Blood PSC 833 concentrationswere determined using the SDZ PSC833 radioimmu-noassay (RIA) kit (ANAWA Laboratories AG, Zurich,Switzerland). On each analysis day, the PSC 833 stan-dard stock solution (12 mg/mL 6 0.2 mg/mL) providedin the kit was diluted with human blood (with ethyl-enediamine tetraacetic acid anticoagulant) to produceseven standard concentrations according to the dilu-tion scheme outlined in the PSC 833 kit instructions.Briefly, standards, quality control (QC) samples,pooled blank normal human whole blood, and patientblood samples were pipetted into prelabeled, 16 mm3 75 mm glass tubes. Each blood sample was analyzedin duplicate. To each sample, 1 mL of methanol wasdispensed, and the sample was vortex mixed and cen-trifuged at 3000 rpm at 40 °C for 10 minutes. Thesupernatant from each tube was decanted into clean,prelabeled 16 mm 3 75 mm glass tubes and evapo-rated to dryness using a vortex evaporator set at 54 °C.To each tube, appropriate volumes of buffer and nor-mal human plasma were added and vortex mixed toredissolve all of the sample residue. To each sampletube, tracer (3H-dihydro-PSC 833) and antibody (spe-cific cyclosporin A monoclonal antibody) were added,vortex mixed briefly, and, after covering, the tubeswere incubated overnight at 4 °C. After placing thesamples in an ice-water bath the next morning, avolume of prechilled charcoal suspension was addedto each sample, and the samples were vortex mixedand incubated at 40 °C for 10 minutes. Each tube wascentrifuged at 3800 g at 4 °C for 7 minutes. Thesupernatant from each sample tube was decanted into10 mL of Picofluor contained in a separate scintillationvial. Each vial was capped, thoroughly mixed, placedin a b counter, and counted for 5 minutes. Each assay

run included the seven blood standard concentra-tions, the maximal binding (B0) samples, totals andnonspecific binding samples, blood samples from pa-tients, and six QC sample concentrations. The QCsample concentrations ranged from 70 ng/mL to 4520ng/mL. Using the internal RIAPROG program, a linearstandard curve was constructed by plotting binding(%B) over B0 versus the standard concentration (Logit-Log). For sample and QC sample concentrationsgreater than the calibration standard concentrations,dilution with blank blood was performed prior to tak-ing an aliquot for analysis. The appropriate volumecorrection factor was applied to the concentrationobserved for diluted samples. The mean PSC 833 con-centration of each set of replicate values was reportedfor all unknowns and QC samples; concentrationswere reported in ng/mL.

Vinblastine LevelsPharmacokinetic analyses of vinblastine were per-formed in two independent laboratories; however, thevinblastine assays did not yield interpretable data, andthe results are not included in this report.

Rhodamine Accumulation in CD56 Positive T CellsWhole blood was obtained from each patient in aheparinized syringe. Rhodamine 123 (Sigma, St. Louis,MO) with or without PSC 833 was added to aliquots ofwhole blood to achieve a final rhodamine concentra-tion of 0.5 mg/mL and a PSC 833 concentration of 3mg/mL.18 The blood was incubated for 30 minutes at37 °C in 5% CO2. After the accumulation period, theblood was layered onto lymphocyte separation me-dium and centrifuged at 2000 rpm for 5 minutes. Themononuclear cell layer from each tube was transferredto a separate tube, washed with cold Dulbecco phos-phate-buffered saline (DPBS), resuspended in 200 mLcold DPBS with 2% fetal calf serum, and held at 4 °C.The cells were then stained with phycoerythrin (PE)-labeled CD56 antibody (Becton Dickinson, San Jose,CA) or PE-labeled mouse immunoglobulin G1 (BectonDickinson) as a negative control. After staining, thecells were washed twice and then resuspended inDPBS and kept on ice in the dark until analyzed. AFACSort flow cytometer (Becton Dickinson) with a488-nm argon laser was used to analyze the samples.Rhodamine fluorescence was collected after a 520-nmbandpass filter and PE fluorescence was collected af-ter a 585-nm bandpass filter. At least 5000 events werecollected per sample, and the samples were gated onforward scatter versus side scatter to exclude clumpsand debris. Dead cells were excluded based on pro-pidium iodide staining.


RESULTSPatient CharacteristicsTable 1 summarizes the diagnosis, performance sta-tus, age, and prior therapy of patients enrolled on thetrial. Emphasis was placed on enrolling patients withrenal cell carcinoma, because a high incidence of Pgpexpression is observed in patients with this malig-nancy. All major histologic subtypes of renal cell car-cinoma were found among patients enrolled on thisstudy. The distribution of these subtypes is included inTable 1, which shows that all patients had a Karnofskyscore $ 70%. Sixty-four of 79 patients had received atleast one prior therapy; 45 of 60 patients with renal cellcarcinoma had been treated previously with interleu-kin 2-containing or interferon-containing regimensand/or other therapies.

Biopsy samples obtained from a subset of thepatients were analyzed for MDR-1 expression byquantitative polymerase chain reaction analysis. Low

levels of expression were observed. These results werepublished elsewhere.19

PSC 833 ToxicitiesTable 2 presents the dose escalation schedule for PSC833. Also shown are the toxicities observed after theinitiation of PSC 833. Although these toxicities areattributed to PSC 833, it should be stressed that thesepatients had received an infusion of vinblastine in theprevious week. However, the vinblastine dose used(1.2 mg/m2 per day CIV for 5 days) was less than thenormally administered dose and resulted in very littletoxicity, as evidenced by only 5 episodes of Grade 3neutropenia and 1 episode of Grade 4 neutropenia inthe 78 patients. Patients in the first seven dose levelsreceived the PSC 833 as a liquid suspension formula-tion every 12 hours. Ten patients were included in thefirst dose level to allow for lengthening the vinblastineinfusion in Cycle 2, as described above (see Materialsand Methods). Because no toxicity was seen at thisdose level, these patients were grouped together asDose Level 1. Two other schedules of PSC 833 werestudied using the microemulsion administered orallyevery 8 hours and every 6 hours. These more frequentschedules of administration were adopted in an at-tempt to achieve higher trough levels and lower peaklevels of PSC 833. This was desired because reversibleclinical toxicities observed within a few hours of drugadministration were potentially a result of high peaklevels. The chief adverse reactions from PSC 833 wereataxia and paresthesias. Table 2 shows that ataxia(Grade 3 gait) was noted first in a single patient re-ceiving a dose of 8 mg/kg every 12 hours. Subse-quently, ataxia was not noted again until the 16.5mg/kg every 12 hours dose level. In addition, at the16.5 mg/kg every 12 hours dose level, one patientexperienced a grand mal seizure. Hyponatremia with asodium level of 124 mmoL/L was noted during evalu-ation of the seizure. Although the hyponatremia wasrecognized subsequently as toxicity from PSC 833 ad-ministration, in this patient, the recent administrationof furosemide for fluid retention may have contrib-uted to the low sodium level. It was concluded thatthe MTD of PSC 833 had been exceeded. Subse-quently, ataxia was noted in the second cycle in twopatients receiving 15 mg/kg PSC 833 every 12 hours(see Table 3), and it was concluded that this dose alsoexceeded the MTD for the liquid suspension givenevery 12 hours. With the microemulsion formulation,of nine patients who were treated with a PSC 833 doseof 5 mg/kg every 8 hours for 8 days, one patientexperienced Grade 4 constipation in Cycle 1, and onepatient had Grade 3 myalgias and anxiety. Conse-quently, the dose was advanced to 5 mg/kg every 6

TABLE 1Clinical Characteristics of Patients Enrolled in the Study

Characteristic Value

DiseaseRCC 60Adrenocortical carcinoma 5Breast carcinoma 8NHL 2Sarcoma 2Bladder carcinoma 1Ovarian carcinoma 1

Performance status (Karnofsky scale)100 4790 2180 570 6

Age (yrs)18–30 331–50 2351–80 53

Prior therapy (RCC)No. of regimens

0 121 332 73 64 15 —6 1

RegimenIL-2 alone 35IL-2 combinations 14Interferon alone 8IFN combinations 5Chemotherapy 5Other 8

RCC: renal cell carcinoma; NHL: non-Hodgkin lymphoma; IL-2: interleukin 2; IFN: interferon.


TABL

E2

Cycl

e1

Toxi

citie

sAt

trib

utab

leto

PSC

833

Dose

leve

lPS

C83

3m

g/kg

/dos

eNo

.of

patie

nts

Toxi

city

grad

e

Low

Na1

Cons

tipat

ion

Elev

ated

bilir

ubin

Hea

dach

eGa

itPa

rest

hesia

san

dne

uroc

ortic

alNa

usea

Prur

itis

Mya

lgia

s

11

23

41

23

41

23

41

23

41

23

41

23

41

23

41

23

4

1a1.

25q1

2h10

22

——

——

——

——

——

——

——

—1

——

—2

1—

——

——

——

——

—2

2.5

q12h

4—

——

1—

——

——

1—

——

——

——

1—

——

2—

——

——

——

——

——

35.

0q1

2h9

11

—1

——

——

—1

——

——

——

—2

——

—1

——

——

——

——

——

—4

8.0

q12h

6—

1—

——

—2

1—

2—

——

——

1—

32

——

——

——

——

——

1—

——

512

.5q1

2h8

21

1—

——

11

1—

——

—1

1—

—5

2—

—1

1—

—1

——

——

——

—6

15.0

q12h

41

——

——

—1

——

——

——

——

——

11

——

2—

——

——

——

——

——

716

.5q1

2h3

——

——

——

11

—1

——

—1

11

—4

——

1—

——

——

——

——

——

—8b

4.0

q8h

9—

——

——

—2

3—

21

——

11

——

7—

——

4—

——

——

——

11

——

95.

0q8

h9

31

—1

1—

14

24

——

——

2—

—7

——

—1

1—

—2

11

——

—1

—10

5.0

q6h

32

——

——

—1

2—

11

——

——

2—

2—

——

1—

——

——

——

——

——

114.

0q6

h13

32

11

——

34

32

——

——

—2

—12

1—

—5

1—

——

——

—1

—1

—To

tal

—79

—8

24

1—

1216

614

2—

—3

56

—45

6—

119

4—

—3

11

—3

12

—

q:Ev

ery;

h:ho

ur.

aPa

tient

sin

levels

1–7

rece

ived

the

liqui

dfo

rmul

atio

nin

aq

12h

sche

dule.

bPa

tient

sin

levels

8–11

rece

ived

the

micr

oem

ulsio

nin

eith

era

q6h

orq8

hsc

hedu

le.


hours for 8 days, at which level ataxia was identifiedagain as the DLT. This prompted a reduction of thePSC 833 dose to 4 mg/kg every 6 hours for 8 days, adose level that was well tolerated by 10 of 13 pa-tients.

Grade 3– 4 hyperbilirubinemia was observed infour patients receiving the liquid suspension every 12hours, a much less frequent incidence than that re-ported previously with cyclosporin A.16,20 However,with the change in formulation and schedule, the fre-quency of hyperbilirubinemia increased substantially.This included one patient with an apparently idiosyn-cratic reaction to the PSC 833 who had severe, slowlyresolving hyperbilirubinemia and pruritus. However,

hyperbilirubinemia was not considered a DLT. OtherPSC 833 toxicities identified included headache, nau-sea, and myalgias. Less frequent toxicities includedchest pressure, anxiety, and Grade 3 hypertension intwo patients.

The MTD of oral PSC 833 for each schedule was12.5 mg/kg every 12 hours for 8 days with the liquidformulation and 5 mg/kg every 8 hours for 8 days or 4mg/kg every 6 hours for 8 days with the microemul-sion. The lower total dose of PSC 833 that was toler-ated when the drug was formulated as a microemul-sion is consistent with independent studies that foundan oral bioavailability nearly double that of the liquidformulation.21,22

TABLE 3Dose Limiting Toxicities of the Vinblastine/PSC 833 Combination Administered during Cycle 2a

Dose level

Cycle 1 Cycle 2

PSC 833mg/kg/dose

No. ofpatients

PSC 833mg/kg/dose

Vbl(mg)

No. ofpatients Dose limiting toxicities

Liquid formulation1 1.25 q12h 10 1.25 q12h 1.2 8 —2 2.5 q12h 4 2.5 q12h 1.2 3 Grade 3 esophagitis, Grade 3 myalgiab

3 5.0 q12h 9 2.5 q12h 1.2 1 Grade 3 constipation3 — — 2.5 q12h 0.9 3 Grade 3 arthralgia3 — — 5.0 q12h 0.9 4 —4 8.0 q12h 6 8 q12h 0.9 5 —5 12.5 q12h 3 12.5 q12h 0.9 3 —6 15.0 q12h 4 15 q12h 0.9 4 Grade 3 paresthesias, Grade 3 gait7 16.5 q12hc 3 15 q12h 0.9 1 Grade 3 gait7 — — 12.5 q12h 0.9 1 —MTD 12.5 q12h 5 12.5 q12h 0.9 5 Grade 4 hyponatremia

Microemulsion8A 4.0 q8h 4 4 q8h 0.9 4 F & N

Grade 4 hyponatremia9A 5.0 q8hd 2 4 q8h 0.9 18B 4.0 q8hd 5 4 q8h 0.9 1 Grade 4 constipation, F & N8B 4 q8h 0.6 4 Grade 4 constipation9B 5.0 q8hd 7 5 q8h 0.6 7 Grade 3 anxiety10 5.0 q6he 3 5 q6h 0.6 1 F & N

4 q6h 0.6 2 —11 (MTD) 4.0 q6h 13 4 q6h 0.6 10 Grade 3 gait

Grade 3 hypertension11 — — 3 q6h 0.6 1 Grade 3 hypertension11 — — 2 q6h 0.6 1 ANC , 500 . 4 daysTotal — 78 — — 70 —

Vbl: vinblastine; q12h: every 12 hours; q8h: every 8 hours; q6h: every 6 hours; MTD: maximum tolerated dose; ANC: absolute neutrophil count.a Vinblastine dose reductions were required during PSC 833 dose escalation. The dose level of PSC 833 at which patients initially were enrolled is indicated under Cycle 1. Patients experiencing Grade 3 gait

disturbance (ataxia) discontinued the PSC 833 and restarted it at a lower dose. If this dose was tolerable, then it was administered in Cycle 2, as shown.b Dose limiting toxicities from a single patient are represented on a single line, e.g. Grade 3 esophagitis, Grade 3 myalgias were observed in a single patient. Dose limiting toxicities resulting in need to decrease

vinblastine dosage are shown in bold.c Dose level 7: Three patients received 16.5 mg/kg q12h in the first cycle. One patient who had a grand mal seizure did not have further therapy. The other two patients had the dose reduced to either 15 mg/kg

q12h or to 12.5 mg/kg q12h for Cycle 2.d Dose level 9A: Two patients treated at 5 mg/kg q8h had dose limiting toxicities; however, one of these patients with Grade 4 hyperbilirubinemia accompanied by pruritis was considered to have an idiosyncratic

reaction. Thus, after an additional 4 patients were shown to safely tolerate the combination of 4 mg/kg q8h PSC 833 and 0.6 mg/m2 vinblastine (level 8B), the dose of PSC 833 was increased again to 5 mg/kg q8h

(level 9B).e Two of three patients enrolled on dose level 10 experienced ataxia and required reduction of the PSC 833 dose to 4 mg/kg q6h.


Toxicities of the CombinationAll patients received a vinblastine dose of 1.2 mg/m2

per day CIV separately from PSC 833 in the first cycle.The first three patients received this dose by continu-ous infusion for 72 hours, and this was increased incohorts of three patients to a 96-hour infusion andthen to a 120-hour infusion. The 120-hour infusionwas then administered to all patients, including thosewho received lower doses of vinblastine combinedwith PSC 833 in the second cycle, when both drugswere administered together. Table 3 presents the vin-blastine dose de-escalation that was required whenvinblastine was administered in combination withPSC 833 in Cycle 2. Seventy of 78 patients who wereevaluable for PSC 833 toxicity received at least thesecond cycle (first combined cycle); 8 patients did notreceive a second cycle for the following reasons: 1)quality of life (3 patients), 2) rapidly progressive dis-ease (2 patients), and 3) PSC 833 toxicity (ataxia at 8mg/kg every 12 hours in 1 patient; Grade 4, slowlyresolving hyperbilirubinemia at 5 mg/kg every 8 hoursin 1 patient; and Grade 4 neurocortical toxicity withseizure at 16.5 mg/kg every 12 hours in 1 patient).Thus, in only 70 patients was it possible to evaluatethe toxicity of the vinblastine plus PSC 833 combina-tion. Among these 70 patients, any patient who hadexperienced DLT due to PSC 833 in the first cycle hadthe PSC 833 dose reduced to a tolerable level. Thisdose was then administered in the second cycle and insubsequent cycles. The DLTs listed in Table 3 includethose ascribed to PSC 833 and/or vinblastine. How-ever, only DLTs attributed to vinblastine resulted in adecrease in the vinblastine dose. A reduction was re-quired as early as the second dose level for patientswith Grade 3 esophagitis and Grade 3 constipation.This lower dose of 0.9 mg/m2 vinblastine per day CIVfor 5 days was tolerated by patients in the ensuing fivedose levels, including those receiving the MTD of theliquid formulation, 12.5 mg/kg of PSC 833 adminis-tered every 12 hours. Changing the formulation andthe administration schedule of PSC 833 resulted in afurther reduction in the vinblastine dose. With theadministration of a PSC 833 dose of 4 mg/kg every 8hours, a reduction in vinblastine dose to 0.6 mg/m2

per day CIV for 5 days was required. Three patientsexperienced neutropenia with fever, Grade 4 hypona-tremia, or Grade 4 constipation at the 0.9 mg/m2 vin-blastine per day CIV for 5 days dose. The reduced dosewas tolerated by subsequent patients even when theadministration of PSC 833 was modified to an every-6-hour schedule. Constipation (all grades) was a fre-quent toxicity for the combination of PSC 833 andvinblastine. Ultimately, a prophylaxis regimen was de-

veloped that reduced the occurrence of severe consti-pation.

PSC 833 PharmacokineticsWhole blood PSC 833 concentrations were measuredin 60 patients during Cycle 1. Figure 2A presents themeasured peak PSC 833 levels, and Figure 2B presentsthe trough levels. Interpatient variability is reflected inthe standard deviations. The mean peak (Fig. 2A) andtrough (Fig. 2B) concentrations increased after chang-ing the formulation to the microemulsion despite thelower administered dose. Peak and trough concentra-tions for the liquid suspension administered at a doseof 15 mg/kg every 12 hours were 2.24 mg/mL 6 0.86mg/mL and 0.61 mg/mL 6 0.45 mg/mL, respectively,compared with 4.09 mg/mL 6 1.27 mg/mL and 2.73mg/mL 6 1.08 mg/mL, respectively, for the microemul-sion administered at a dose of 4 mg/kg every 6 hours.These results are consistent with the known higheroral bioavailability of the microemulsion.21,22 The cal-culated PSC 833 pharmacokinetic parameters areshown in Table 4. The most striking finding was largeinterpatient variability in calculated pharmacokineticparameters with both formulations and all schedules.There was no evidence of dose dependent clearanceover the dose ranges examined with the every-12-hours dosing regimen or with the every-8-hours andevery-6-hours regimens. At the MTD of the micro-emulsion (4 mg/kg every 6 hours for 8 days), theclearance was estimated at 14.83 liters per hour, witha terminal half-life of 28.95 hours (range, 6.75– 454.8hours). Whether patients with ataxia had higher bloodlevels could not be determined, because dose limitingataxia occurred at home, and treatment was discon-tinued prior to return to the hospital, where therapywas reinstituted at a lower PSC 833 dose prior topharmacokinetic sampling.

Clinical CorrelatesThe clinical observation was made that the incidenceof hyperbilirubinemia in Cycles 1 and 2 increasedwhen the formulation was changed to the microemul-sion and the schedule was changed to every 8 hoursand every 6 hours. Episodes of hyperbilirubinemia$ Grade 2 occurred in 20% of patients receiving theliquid solution every 12 hours and in 43% of thosereceiving . 16 mg/kg per day on an every-12-hoursschedule. By comparison, 66% and 80% of patients onthe every-8-hours and every-6-hours schedules, re-spectively, had hyperbilirubinemia. To determinewhether this increase in bilirubin was due to increasedexposure to PSC 833, a regression analysis was per-formed using bilirubin levels obtained in the last 24hours of PSC 833 administration and the peak and


FIGURE 2. Peak (A) and trough (B)

PSC 833 concentrations as a function of

administered dose. Statistical analysis

demonstrated that both peak levels and

trough levels on the schedule of PSC

833 4 mg/kg every 6 hours (q6h) for 8

days were significantly different from

levels from the schedule of PSC 833

12.5 mg/kg every 12 hours (q12h) for 8

days (P 5 0.004 and P 5 0.0006, re-

spectively). Open circles: peak (A) and

trough (B) concentrations of PSC 833 for

each patient on each dose level; solid

circles and horizontal lines: mean and

standard deviation, respectively; aster-

isks: points excluded from mean and

standard deviation calculations; arrows:

point of change in formulation from liq-

uid to microemulsion.


trough concentrations of PSC 833. Poor regressioncoefficients (r2 5 0.27 for peak levels and r2 5 0.25 fortrough levels) suggest that hyperbilirubinemia was notrelated to absolute PSC 833 blood concentrations but,instead, reflected interindividual variation indepen-dent of blood levels. Poor regression coefficients alsowere obtained when the regression analysis was per-formed using the change in bilirubin levels from base-line instead of absolute bilirubin levels. However, themicroemulsion formulation used in the every-8-hoursand every-6-hours schedules was more likely to beassociated with hyperbilirubinemia.

Response EvaluationAlthough the trial was a Phase I study, efforts weremade to recruit patients with renal cell carcinoma, adisease associated with a high incidence of Pgp ex-pression. Table 5 presents the response data for thepatients with renal cell carcinoma. Three patients ex-perienced a complete response, and one patient ex-

perienced a partial response. In addition, two patientshad reductions in tumor size of 40% and 35%, notreaching the criteria for a partial response, and 10patients had stable disease of . 5 months duration.The patient with a partial response was rendered freeof disease by resection of a residual periaortic abdom-inal lymph node after all pulmonary disease had re-sponded. This patient remained free of disease an-other 21 months before the recognition of two small,enlarging, pulmonary nodules that were resected. Theother three patients have been free of disease for 40months, 79 months, and 88 months.

T CellsInhibition of rhodamine efflux from CD56 positivecells was used as a surrogate marker. The results in 10patients who were enrolled at the MTD of PSC 833 (4mg/kg every 6 hours for 8 days) are shown in Figure 3.The extent of rhodamine efflux from CD56 positivecells before the start of treatment compared with that2 hours after the first oral dose of PSC 833 for arepresentative patient is shown in Figure 3A and B,respectively. A previous study demonstrated that, al-though the effect on the efflux period was greatest,variability was least after the accumulation period;18

thus, the difference in mean channel number betweenthe control and PSC peaks is plotted on the y-axis foreach sample in Figure 3C. Inhibition of efflux, mani-fested as marked retention of rhodamine in CD56positive cells, was seen in all patients.

DISCUSSIONThis study presents the results of a Phase I study ofPSC 833 in combination with vinblastine. Two PSCformulations and three dosage schedules were inves-tigated. PSC 833 toxicities were similar to those re-ported by other investigators and consisted primarily

TABLE 5Responsesa

ResponseClearcell RCC

Non-clearcell RCC

Othermalignancies

CR 3 — —PR 1 — —SD 9 3 2PD 27 9 6NE 3 5 10Total 43 17 18

RCC: renal cell carcinoma; CR: complete response; PR: partial response; SD: stable disease; PD:

progressive disease; NE: not evaluable.a Responses were defined according to standard criteria. Stable measurements for 5 months were

required to be considered SD.

TABLE 4Pharmacokinetic Parameters for PSC 833

LevelNo. ofpatients

Dose(mg/kg) Schedule Formulation Vd/F (liters)a CL/F (liters per hour)a T 1/2-a (hours)a T 1/2-b (hours)a

1 6 1.25 q12h Liquid 12.18 (3.01–56.01) 9.42 (5.82–26.49) 0.63 (0.08–1.62) 80.14 (0.27–312.1)2 4 2.5 q12h Liquid 63.50 (1.27–94.55) 42.07 (0.57–69.9) 0.28 (0.03–1.99) 12.06 (0.292–79.58)3 7 5 q12h Liquid 31.33 (4.86–158.8) 26.63 (20.83–51.89) 0.18 (0.04–1.6) 36.46 (2.75–307.6)4 5 8 q12h Liquid 8.77 (3.83–45.76) 13.58 (2.84–34.89) 0.17 (0.06–1.49) 38.35 (16.93–123.6)5 4 12.5 q12h Liquid 40.42 (24.63–87.32) 43.23 (14.63–51.6) 0.47 (0.10–0.80) 57.96 (27.31–257.5)6 5 15 q12h Liquid 31.56 (2.77–141) 57.32 (44.33–91.93) 0.29 (0.02–0.32) 60.44 (11.79–203.8)7 11 4 q8h Microemulsion 15.30 (2.68–53.28) 13.62 (7.90–42.55) 0.57 (0.17–1.85) 3.59 (0.59–98.77)8 9 5 q8h Microemulsion 8.53 (4.16–35.89) 19.11 (12.48–31.76) 0.28 (0.06–1.01) 4.23 (1.76–197.7)9 9 4 q6h Microemulsion 25.01 (5.65–74.78) 14.83 (6.60–21.39) 0.65 (0.06–1.89) 28.95 (6.75–454.8)

q12h: every 12 hours; q6h: every 6 hours. Vd/F: volume of distribution of central compartment; CL/F: oral clearance; T1⁄2-a: distribution half-life; T1⁄2-b: elimination half-life.a Median values are shown, with ranges indicated in parentheses.


of ataxia and paresthesias. The MTD of the final com-bination was 4 mg/kg PSC 833 every 6 hours for 8 dayswith vinblastine administered CIV at 0.6 mg/m2 perday for each of 5 days. The DLTs of the combinationwere fever, neutropenia, and Grade 4 constipation.The chief concern for this combination is whether theMTD for vinblastine administered in combinationwith the MTD of the Pgp antagonist reflects blood andtissue concentrations of vinblastine that are equal tothose found at the MTD for vinblastine administeredalone. Among 60 patients with renal cell carcinoma,there were 3 complete remissions and 1 partial remis-sion.

We identified 4 mg/kg every 6 hours for 8 days asthe MTD of PSC 833, a lower dose for this schedulethan the dose level of 5 mg/kg every 6 hours deter-mined in other studies.23,24 This lower dose may bedue to the enrollment of patients with renal cell car-cinoma, many of whom had only one kidney, or po-tentially due to strict adherence to the requirementthat PSC 833 be ingested on an empty stomach. Twoof three patients who were treated at a dose of 5 mg/kgevery 6 hours experienced ataxia.

Delays in anticancer drug clearance have beenobserved previously with Pgp antagonists, most nota-bly cyclosporine and PSC 833, but also have beennoted with other second-generation Pgp antagonists,such as VX 710.25 In humans, PSC 833 has been shownto delay paclitaxel clearance, increasing half-life two-

fold and requiring a dose reduction to one-half orone-third of the usual systemic dose.26 –28 Similarly,the interaction with etoposide required a 25% dosereduction,29 as did the interaction with doxorubi-cin.30,31 Larger etoposide reductions were requiredwhen PSC 833 was added to a combined regimenconsisting of mitoxantrone plus etoposide or mitox-antrone plus etoposide and cytosine arabinoside, sothat the tolerable dose was a 66% reduction comparedwith the MTD without PSC 833.32,33 These reductionsin dose reflect the reduced clearance and increasedareas under the concentration curves (AUCs) of thechemotherapeutic agents due to the addition of PSC833. The mechanisms of this pharmacokinetic inter-action are potentially both competitive inhibition ofcytochrome P450 (the principal pathway of PSC 833metabolism) and/or inhibition of Pgp-mediated drugtransport in the normal liver and kidney. PSC 833 islike many other compounds that are known to be bothsubstrates for Pgp and also substrates for metabolismby the P450 pathway.9 Pgp-interacting compounds,such as anthracyclines, vinca alkaloids, taxanes, andepipodophyllotoxins, are metabolized by P450; thus,inhibition of P450 by PSC 833 may be responsible fordelayed drug clearance.8,34 However, studies in micein which the mouse orthologues for MDR-1 were de-leted have shown decreased drug clearance and anincrease in drug accumulation particularly in thebrain, indicating that, in the mouse model, Pgp inhi-

FIGURE 3. Effect of PSC 833 on rhodamine efflux from CD56 positive cells in 10 patients who received PSC 833 4 mg/kg every 6 hours. (A) Rhodamine

fluorescence in CD56 positive cells obtained from a patient before the administration of PSC 833. Cells were incubated without rhodamine (Blank) or with rhodamine

(Control) or with rhodamine and the addition of exogenous PSC 833 (PSC). These cells were placed on ice for analysis, whereas duplicate samples were washed

and placed in rhodamine free media for a 60-minute efflux period without PSC 833 (Efflux) or with PSC 833 (PSC-Efflux; not shown). (B) The same assay performed

in CD56 positive cells obtained from a patient 2 hours after the administration of PSC 833. (C) The difference between the mean channel numbers for PSC and

control samples is plotted on the y-axis. Samples obtained prior to ingestion of PSC 833 (Pre) and 2 hours after the first dose of PSC 833 are compared in 10 patients.

The reduction in mean channel difference is due to the effective inhibition of rhodamine efflux from CD56 positive cells by circulating PSC 833.


bition alone is sufficient to alter pharmacokinet-ics.11,12,35

In the current trial, the vinblastine MTD of 0.6mg/m2 per day CIV for 5 days was one-half to one-third the dose that can be administered safely in theabsence of an antagonist.5 This compares with a pre-vious trial combining cyclosporine A with a 4-dayinfusion of vinblastine in which the MTD of vinblas-tine was 1.2 mg/m2 per day CIV for 4 days.15 Althoughthe doses for both vinblastine and PSC 833 were de-termined according to standard Phase I criteria, ad-justments in the vinblastine dose were allowed forindividual cycles depending on how the patient hadtolerated the previous cycle. Consequently, even at theMTD of PSC 833, the dose of vinblastine administeredranged from 0.6 mg/m2 to 1.2 mg/m2 per day CIV for5 days. This interpatient variability may have been dueto differences in the extent of drug interaction, pre-sumably at the level of P450. Interpatient variations inP450 interactions are well known, and assays havebeen developed to quantitate these differences.36,37

Indeed, clearance mediated by P450 has been re-ported to vary ten-fold among patients.38 It may bepossible to predict differences in P450 interactionsand, thus, improve drug dosing. The latter would beespecially valuable, because the approach used in thecurrent study was gradual escalation of the dose inindividual patients. This approach results in the ad-ministration of suboptimal doses in the initial cyclesand, by itself, may induce drug resistance. In the cur-rent study, increases were needed in as many as one-half of the patients who received a third cycle.

The need to significantly reduce the dose of vin-blastine administered in combination with PSC 833raises concerns about the comparability of steady-state concentrations in patients receiving the combi-nation compared with patients receiving vinblastinealone. Although equitoxicity was achieved with thedose reduced vinblastine, it is unclear whether thiswas a result of comparable AUCs rather than similarpeak or steady-state concentrations. If a prolongedterminal half-life results in low concentrations of vin-blastine, then toxicity may result without efficacy. Oneexample of such an interaction was found in a studycombining VX 710 with paclitaxel.25 The administra-tion of VX 710 with reduced doses of paclitaxel re-sulted in AUCs that were comparable to those pub-lished for single-agent paclitaxel. However, the Cmaxvalues were reduced by 30%. If the AUC is calculatedto infinity, then a long terminal half-life may result inAUC calculations that are comparable despite actualdecreases in steady-state levels. An important goal forPgp reversal studies should be the achievement ofcomparable AUCs over more relevant intervals.

To aid in interpreting the outcome of trials withPgp antagonists, three ancillary studies have been de-veloped. These studies evaluate whether Pgp inhibi-tion is occurring in patients: 1) 99Tc-sestamibi imagingof tumors and the normal liver;39 2) ex vivo assaysusing mononuclear cells from patients;18 and 3) exvivo assays using patient serum.40 The first two ofthese were used in the current study. Sestamibi imag-ing in a small cohort of patients confirmed increasedretention of tracer both in the liver and in isolatedpulmonary metastases after treatment with PSC 833.41

Marked retention of 99Tc-sestamibi in the liver wasobserved in all patients studied without significantefflux through the end of the scanning period 6 hoursafter administration of tracer. Retention of 99Tc-sesta-mibi also was observed in imaged tumors. These re-sults parallel observations in other studies demon-strating increased 99Tc-sestamibi retention with Pgpantagonists in both clinical models and animal mod-els.39,41– 43 Although they do not directly confirm in-creased levels of vinblastine in tumors, the resultsconfirm that PSC 833 is capable of increasing theaccumulation of Pgp substrates in tumor tissue and ofdelaying clearance of the tracer from the liver.

The second assay used CD56 positive cells to de-tect the extent of in vivo Pgp inhibition. In this assay,the patient’s mononuclear cells obtained pre-treat-ment and post-treatment with PSC 833 are incubatedex vivo with the Pgp substrate rhodamine 123.18,44

Efflux of rhodamine 123 is blocked by PSC 833, result-ing in higher levels of fluorescence in the patient’scells after treatment. The degree of inhibition of effluxcan be correlated with the PSC 833 level in a patient’splasma. Patients receiving the MTD (4 mg/kg PSC 833every 6 hours) demonstrated inhibition of rhodamineefflux from their CD56 positive cells, indicating in vivoinhibition of Pgp. Similar results were reported forpatients receiving the second-generation antagonistGF120918.44 However, our rhodamine efflux studiessuggested an apparent plateau in the inhibition ofrhodamine efflux at approximately 1000 ng/mL PSC833. Because the median PSC concentration at theMTD was 4000 ng/mL, it appears likely that the MTDdose of PSC 833 exceeded that needed to achieve itsbiologic effect.

The low frequency of responses reflects a problemthat has plagued Pgp reversal trials—few responsescan be attributed clearly to the addition of reversalagents.7 This partially reflects the use of patient pop-ulations that are heavily pretreated prior to enroll-ment on study; or, in the case of the current trial,patients with intrinsically refractory disease. In addi-tion, the responses observed in the first-generationtrials could not always be attributed to the Pgp antag-


onist because of the delay in clearance of the chemo-therapeutic agent(s) after the addition of the antago-nist. This effectively increased drug exposure,providing a potential explanation for the occasionalresponses observed.45 In two previous trials that ad-ministered a 5-day vinblastine infusion in combina-tion with high-dose tamoxifen or high-dose cyclospor-ine to patients with renal cell carcinoma, there wereno complete or partial responses.16 In the currentstudy, among 60 patients with renal cell carcinoma, 43of whom were evaluable, 3 complete responses and 1partial response were observed. However, the signifi-cance of this is unknown, because high intertrial vari-ability in response rates has been documented in pa-tients with renal cell carcinoma.4

Clinical trials with MDR reversal agents tradition-ally have used the MTD of the blocking agent. Analternate strategy may be to use clinically relevantsurrogates to establish an optimal blocking dose. Thisdose may be lower than that determined using anMTD strategy and may minimize the reduction inclearance of the anticancer compound. This, in turn,may reduce the variability in pharmacokinetic inter-action among individual patients, allowing the maxi-mum dose of the chemotherapeutic agent to be ad-ministered at the outset. The importance of this isunderscored by the recognition that, even under-dos-ing as few as 25% of patients with some malignancies,for example, acute myelogenous leukemia, wouldlikely abolish any gain achieved from the inhibition ofPgp in the remaining patients. This would make itdifficult to identify settings in which the inhibition ofPgp may be useful clinically. This study, as reported inthe first-generation Pgp reversal trials, confirms thesafety of the addition of a potent Pgp antagonist toantineoplastic therapy. The responses observed havebeen durable, suggesting that the combination is po-tentially effective in patients with renal cell carci-noma.

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Documents

A Phase I study of infusional vinblastine in combination with the p-glycoprotein antagonist PSC 833 (valspodar)