(CANCER RESEARCH 49, 1063-1066, February 15, 1989]

Clinical Trial of Continuous Infusion Verapamil, Bolus Vinblastine, and ContinuousInfusion VP-16 in Drug-resistant Pediatrie Tumors1

Mitchell S. Cairo,2 Stuart Siegel, Nick Anas, and Leonard Sender

Divisions of Hematology-Oncology and Critical Care, Childrens Hospital of Orange County, University of California, Irvine [N. A.], Childrens Hospital of Los Angeles,University of Southern California [S. S., L. S.]

ABSTRACT

We optimized the modulation of drug resistance by the irreversibleaugmentation of cytotoxicity of coincubating vinblastine (VNB) with VP-16 and the reversible increase in cytotoxicity of coincubation of verapamil(VPL) with VNB and VP-16. VPL was administered as a loading dose(i.v.) (0.15 mg/kg) and then administered as a constant infusion (0.005mg/kg) over 6 days. 24 h after verapamil, VNB 2 mg/m2 IVP wasadministered and followed l h later by a 5-day simultaneous continuousinfusion of VP-16 (200 mg/m2/day) to seven pediatrie patients (11

courses) with refractory malignancies. The mean age at treatment was7.5 ±5.3 years, mean prior anthracycline dose (303 ±210 me/in') with

a range of 0-606 mg/m2. Toxicity was limited to cardiac and hematolog-

ical. The median nadir of the VVBCwas 900 at 14.5 ±0.5 days andplatelet count 32,000 at 15.5 ±0.8 days. There were two episodes ofbacterial sepsis both of which responded to i.v. antibiotics. Five of 11courses resulted in first-degree block and one course in second-degreeblock. At Hour 120 of the VPL infusion the PR interval was 0.18 ±0.01versus 0.13 ±0.01 at Hour O(P < 0.0004). The ejection fraction by two-dimensional echocardiogram was not significantly different at Hour 0,24, or 120 of the infusion (60.6 ±2.7 versus 52.7 ±5.1 versus 51.8 ±5.0%). The cardiac index was also not significantly different at Hour 0,24, or 120 (4.39 ±0.2 versus 4.21 ±0.6 versus 3.91 ±0.5 liters/min/m2).

The 15-min VPL level was 1954.5 ±391/ng/ml and steady state levelsat Hour 24 and 120 of the infusion were 468.1 ±59 and 422.8 ±52 ng/ml, respectively. Two of 11 treatment courses resulted in hypotensionsecondary to inordinately high 24-h levels of VPL (1233 and 1263 ng/ml). These two episodes required inotropic support but did not requirethe discontinuation of VPL. There were 8 of 11 partial responses, themajority of which consisted of peripheral cytoreduction of leukemic blastsand one M-2A response in AML. The levels of VPL achieved in thisstudy have been shown to augment the in vitro cytotoxicity of vinblastineand VP-16 to resistant cell lines. Further clinical studies are needed todetermine the maximal-tolerated dose of VPL in a Phase I study and toexamine its efficacy in selected relapsed pediatrie patients.

INTRODUCTION

The development of drug resistance during the use of chemotherapy is a major factor limiting the success of anticanceragents. Resistance to multiple chemotherapeutic drugs is acommon clinical problem in the treatment of malignancies;such resistance may occur during primary therapy or be acquired during subsequent treatment. There are numerous described mechanisms of resistance to cytotoxic drugs. Many ofthese can be attributed to be either an alteration of drug entryinto the cell, drug binding to a target site, intracellular drugactivation or inactivation, or drug efflux (1). One of the mostcommon of these mechanisms is the development of MDR3 (2).

Received 5/23/88; revised 10/3/88; accepted 11/11/88.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 inaccordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1This project was supported with a grant from The Pediatrie Cancer ResearchFoundation of Orange County. This study was presented in part at the ClinicalInvestigative Section of the American Association of Cancer Research meetings,May, 1988, New Orleans, LA.

2To whom requests for reprints should be addressed, at Childrens Hospital of

Orange County, 455 South Main Street, Orange, CA 92668.3The abbreviation used is: MDR, multiple-drug resistance; EKG, electrocar

diogram; PR, interval between P and R wave.

A gene responsible for the development of MDR has recentlybeen identified (3). This MDR gene appears to encode for a M,170,000 glycoprotein found in the plasma membrane, termedp-glycoprotein (4). The increased expression of the p-glycopro-tein on resistant tumor cells has been associated with reduceddrug accumulation and increased drug efflux (4). This increasein drug efflux has resulted in a decrease of drug accumulationand subsequent reduction of in vitro cytotoxicity.

A number of biochemical agents have been found to overcomemultiple-drug resistance by inhibiting drug efflux and allowingcytotoxic chemotherapy to accumulate within resistant cells (5).Verapamil, a calcium antagonist, has been demonstrated toovercome multiple-drug resistance in many experimental resistant cancer cell lines (6). Verapamil is currently used in thetreatment of supraventricular cardiac arrthymias (7) and anginapectoris (8). Verapamil, however in addition to its cardiac effect,has also been shown to overcome resistance of Vinca alkaloids,i.e., vincristine and vinblastine, anthracyclines, and epipodo-phyllotoxins, i.e., VP-16 and VM-26 against various resistantmurine and human tumor cell lines by reversibly inhibiting drugefflux of these drugs (6, 9-14).

Yalowich et al. (15) have recently demonstrated that a micro-tubular inhibitor such as vinblastine can enhance the cellularaccumulation of VP-16 by inhibiting the efflux of the nonex-changeable pool of VP-16. This accumulation of VP-16 isassociated with increased in vitro cytotoxicity of the humanleukemia cell line, K562, and requires only a brief exposure ofvinblastine. Following coincubation of VP-16 with vinblastine,there is an increase in the cellular accumulation of VP-16 andan increase in its in vitro cytotoxicity. This modulation ofcytotoxicity by vinblastine has been determined to be an irreversible process.

To optimize the modulation of drug resistance from theabove-mentioned studies, we developed a clinical study examining the combination of verapamil, VP-16, and vinblastinebased on the above observations. The objective of this trial wasto determine the cardiac toxicity that could be expected at aparticular dose of verapamil in refractory pediatrie cancer patients. Unfortunately the technology of diagnosing multiple-drug resistance was not available at the time these patients wereinitially diagnosed. Since most of these patients relapsed ontherapy with chemotherapy associated with MDR, an assumption was made that some or all of these patients theoreticallyrelapsed from initial therapy secondary to MDR. The primaryobjective of the study was not to assess response but thefeasibility of using verapamil in conjunction with chemotherapyin doses previously applied in similar adult patients. All patientshad normal baseline EKGs and left ventricular ejection fractions and cardiac indexes by two-dimensional echocardiograms.Subsequent EKGs, left ventricular ejection fractions, and cardiac indexes were obtained 24 and 120 h during the treatmentprotocol. Hematological, hepatic, and renal toxicity were alsomonitored at baseline and during this study.

MATERIALS AND METHODS

Patients. Seven pediatrie patients with refractory malignancies weretreated during 11 separate courses with this treatment protocol. The

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VERAPAMIL-, VP-16-, V1NBLASTINE-RELAPSED PEDIATRIC TUMORS

age, diagnosis, and description of previous chemotherapeutic regimensin this group are outlined in Table 1. All patients had failed priorcombination chemotherapy regimens and four of seven patients hadprior exposure to VP-16 and additionally to vincristine. Six of sevenhad prior anthracycline exposure, and their total cumulative dose priorto entrance on this study is noted in Table 1.

Treatment Protocol. All patients were admitted for therapy to thePediatrie Intensive Care Unit of Childrens Hospital of Orange County.This treatment protocol was approved by the CHOC Human SubjectsReview Committee (Institutional Review Board). Continuous cardiovascular monitoring was conducted throughout the treatment course,including blood pressure, heart rate, and rhythm and serial EKGs andechocardiograms. The patients were treated on a 6-day treatmentcourse. On Day 0, verapamil was administered as an i.v. bolus of 0.15mg/kg, and this was followed by a continuous infusion of verapamil at0.005 mg/kg/min. This dose was extrapolated from Ozol's (25) study

in adult ovarian carcinoma patients. This dose was chosen to be studiedin children to determine if similar cardiac toxicity occurred in refractorypediatrie cancer patients. After 24 h of continuous infusion verapamil,vinblastine was administered as an i.v. bolus 2 mg/m2, l h after thebolus of vincristine, VP-16 was begun as a constant infusion of 200mg/m2/day for 5 days for a total of 1000 mg/m2. The verapamil infusionwas continued throughout the bolus of vincristine and 5-day infusionof VP-16. Verapamil levels were obtained 15 min after the initial bolusinjection and at 24 and 120 h of the continuous infusion. Plasmaverapamil levels were measured by high pressure liquid chromatography(16).

Statistical Analysis. Statistical analysis was performed using theStudent's t tests for the comparison of groups studied. A P value of

0.05 is considered significant. ±represents standard error of the mean(SEM).

RESULTS

Organ Toxicity (Noncardiac). The age and diagnosis of theseven patients and 11 treatment courses are outlined in Table1. The mean age was 7.5 ±5.3 years, range (2.5 to 17 years).There were eight treatment courses for relapsed leukemias andthree courses for solid tumors. The mean dose of prior anthracycline therapy was 303.5 ±210 mg/m2 (range, 0-686 mg/m2).

There were no episodes of either renal or hepatic toxicity duringthe 11 treatment courses. Four of the 11 treatment cyclesresulted in grade IV hematological toxicity (Absolute Neutro-phil Count <500/mm3 or platelet count <20,000/mm3), most

of which occurred in the leukemia patients who were in relapseat the time of treatment. The median nadir of the WBC countwas 900 (range, 100-5,400) at 14.5 ±0.5 days and mediannadir of the platelet count was 32,000 (range, 4,000-280,000/mm3) at 15.5 ±0.8 days. There were two episodes of sepsis

following treatment, both of which responded to i.v. antibiotics.Cardiac Toxicity. Serial EKGs revealed that five of 11 courses

resulted in first-degree heart block and one treatment courseresulted in a second-degree heart block, Mobitz type II. AMobitz type II is described as a prolongation of the PR intervalwith dropped QRS complex on EKG and its significance is that

it may be a precursor to complete heart block. The mean PRinterval at Hour 0 was 0.13 ±0.01. At Hour 120 of theverapamil infusion, the PR interval was significantly higher, P< 0.0004 (Table 2). The mean ejection fractions were lower butstill above 50% and not statistically different at Hour 24 andHour 120 of the infusion (52.7 ±5% and 51.8 ±5.0%),respectively. The cardiac index fell slightly, but remained in thenormal range both at Hour 24 and Hour 120 of the verapamilinfusion (4.2 ±0.6 and 3.9 ±0.5 liter/min/m2), respectively

(Table 2). Two of 11 treatment courses resulted in significanthypotension requiring dobutamine (10 Mg/kg/m in) or dopamine(5 Mg/kg/min) for inotropic support. Both of these toxic treatment cycles were secondary to inordinately high levels of verapamil (Table 3). In the first patient with cardiac toxicity(Course I toxicity) similar doses of verapamil were given in aprevious course and resulted in verapamil levels at Hours 24and 120 of 670 and 572 ng/ml compared to the second treatment course which resulted in toxic levels of 1233 and 933 ng/ml. In the second patient (course II toxicity) with cardiactoxicity, similar doses of verapamil were given in a previouscourse resulting in verapamil levels at Hours 24 and 120 of 380and 484 ng/ml, respectively, compared to the second treatmentcourse which resulted in toxic levels of 1263 and 870 ng/ml.All 11 cycles of therapy were completed and none requireddiscontinuation of verapamil.

Verapamil Levels. Mean verapamil levels 15 min following abolus injection of 0.15 mg/kg were 1954 ±391 ng/ml. Steadystate verapamil levels were significantly lower at Hour 24 andHour 120 of the infusion but were not statistically differentfrom each other, 468.1 ±59.8 ng/ml versus 422.8 ±52.2 ng/ml (Fig. 1). This study was designed to correlate clinical cardiactoxicity to plasma levels of verapamil and unfortunately wasnot intended to be a pharmacokinetic study. Pharmacokineticstudies of verapamil have been previously described in childrenand adults (17, 18). The two treatment courses which resultedin cardiac toxicity were associated with significantly higherverapamil levels (Table 3). One of these cardiotoxic patientshad a past history of anthracycline cardiotoxicity, which hadpreviously resulted in an episode of congestive heart failure.His echocardiogram and clinical status, however, were in thenormal range prior to his entrance onto this study.

Responses. Although this was a clinical study in highly refractory and end-stage pediatrie oncology patients, clinical responses were measured when appropriate. A partial responsewas defined as a reduction in >25% of the tumor diameter insolid tumors or complete disappearance of peripheral blasts inthe leukemia patients. An M-2A bone marrow was defined asbetween 5-15% blasts in the bone marrow. There was onepartial response with neuroblastoma, 0/2 responses in hepato-blastoma, 3/4 partial responses with cytoreduction of peripheral blasts in acute lymphocyte leukemia, 1/1 partial responsewith cytoreduction of peripheral blasts in juvenile chronic my-

Table 1 Clinical characteristics of clinically résistentpediatrie cancer patients

PatientCM.

T. A.R. B.A.Z.C.

L.H.A.

B. H.DiagnosisStage

IV neuroblastomaAcute myelogenous leukemia (AMI)State IV hepatoblastomaAcute lymphoblasticleukemiaAcute

lymphoblasticleukemiaJuvenile

chronic myelogenous leukemiaAcute myelogenous leukemiaAge

(yrs)2Vi

175Vi84%3%

12Number

ofcourses1

12

2212Previous

MDRchemotherapyVincristine,

VM-26, doxorubicinVincristine, danni »rubicin, VP-16Doxorubicin, VP-16Vincristine, daunorubicin, doxo

rubicinVincristine, daunorubicin, doxo

rubicin, idarubicinVP-16Daunorubicin, vincristine, VP-16Previous

anthracycline(mg/m2)202

2106801351770412

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VERAPAMIL-, VP-16-, VINBLASTINE-RELAPSED PED1ATRIC TUMORS

Table 2 Cardiac effects of VPL°/VNB/VP-16

CardiacmeasurementPR

interval (mm)Ejection fraction (%)*Cardiac index (liter/min/m2)*Normal

range<0.16

3-5,

=0h0.13

±0.0160.6 ±2.14.39 ±0.20r

= 24h0.15

±0.0152.7±5.1

4.21 ±0.60P

valueNS

NSNSt

= 120h0.18

±0.0151.8 ±5.03.91 ±0.50P

valueP

< 0.0004NS

NS" Abbreviations: VPL = vcrapamil, VNB = vinblastine, NS, not significant; PR, interval between P + R wave on EKG.'' Ejection fraction and cardiac index are measured by a two-dimensional echocardiogram.

Table 3 Comparison ofnonloxic and toxic responses to verapamil

Verapamil (ng/ml) Ejection fraction (%)

Hour24

Hour120

Baseline

Hour24

Nine nontoxic courses 468 ±59 422 ±52 60.6 ±2.7Course I—toxicity 1233 933 63Course II—toxicity 1263 870 56

52.7 ±5.051°36*

" Treated with dobutamine 1'' Treated with dopamine 5 fig/kg/min.

2500-r-

15 min.

Fig. 1. Verapamil levels during treatment with vinblastine and VP-16.

elogenous leukemia and 3/3 partial responses in acute myelog-enous leukemia, one of which resulted in an M2-A bone marrow. There were no complete responses and all seven patientseventually expired with progressive disease.

DISCUSSION

In 1981, Tsuruo et al. (11), reported complete recovery ofvincristine cytotoxicity to vincristine-resistant P388 leukemiaby verapamil in vitro and in vivo restoration of vincristineresponsiveness. The same author subsequently reported similarstudies of verapamil enhancing Adriamycin cytotoxicity in anAdriamycin-resistant P388 leukemia cell line in vitro. Verapamil has also been shown to completely reverse vincristine resistance in K.562 leukemia and other human hematopoietic-

resistant cell lines (6).Verapamil has recently been shown to potentiate the fre

quency of DNA strand breaks and cellular cytotoxicity in L1210and K562 leukemias in vitro (9). Subsequent studies have reported that verapamil potentiates VP-16 cytotoxicity by elevation of intracellular exchangeable VP-16 by inhibiting cellularefflux of VP-16. Slater et al. (19) reported that VP-16 andvincristine are potentiated by verapamil to increase their cytotoxicity by 10-fold or greater against K562 cells compared tominimal toxicity against normal human bone marrow progenitor cells (CFU-GM) (20).

Yalowich et al. (15) studied the effects of microtubular inhibitors, including vinblastine, on VP-16 accumulation and DNAstrand breaks in human K562 cells in vitro. Using concentra

tions of vinblastine achievable in vivo (0.05-0.2 UM), there wasa progressive increase in the nonexchangeable pool of VP-16and potentiation of VP-16-induced DNA damage in vitro. Thiseffect was in striking contrast to the effect seen with verapamiland VP-16. In the experiments with vinblastine and VP-16 theenhancement required only a brief, but not a continuous exposure of vinblastine and was found to be an irreversible processeffecting only the nonexchangeable pool of VP-16. This is incomparison to verapamil's effect with VP-16 which is reversi

ble, requires constant exposure, and effects only the exchangeable pool of VP-16.

The concentrations of verapamil required to overcome pleio-tropic drug resistance in vitro have been in the range of 0.5 to10.0 MM/liter (225 to 4225 ng/ml) (5, 6, 9-11, 19, 20). Additionally, the in vitro verapamil levels required to reverse Adriamycin resistance to ovarian cancer lines, developed by a step-wise incubation of the cell line 1847 AD with increasing concentrations of Adriamycin was 250 ng/ml (0.55 /iM/liter). Fine etal. (21) studied the in vitro effects of clinically achievableverapamil levels (250-1000 ng/ml) (0.55 to 2 ^M/liter) onAdriamycin and vincristine inhibition of colony forming unit-granulocyte macrophage colony formation and found no evidence of increased bone marrow cytotoxicity.

Our study achieved steady state concentrations of 468 ±59ng/ml and 422 ±52 ng/ml at Hour 24 and Hour 120, respectively. These levels represent almost 1 ^M of verapamil, levelswhich have been reported to reverse pleiotropic drug resistancein vitro. Continuous infusion verapamil in adults (22) (0.025mg/kg/min), a dose representing 50% of our infusion rate,resulted in verapamil concentrations between 77 and 156 ng/ml, a concentration described to be too low for enhanced invitro cytotoxicity and inhibition of drug efflux. Previous pediatrie studies following a continuous infusion of 0.007 mg/kg/min, reported a wide variation of verapamil pharmacokinetics,with levels ranging from 56 to 304 ng/ml, mean 194.3 ±37(17, 18). Our study substantiates the variable steady state concentration of verapamil infusions in children. Two of our treatment courses resulted in toxic levels of verapamil two to threetimes that compared to the rest of the group.

In adults treated with high doses of verapamil for supraven-tricular tachycardia, a level of 250-1000 ng/ml resulted in anincidence of 10-25% first-degree heart block (23, 24). In thisstudy five of 11 (45%) of our treatment courses resulted in first-degree heart block, none of whom required discontinuation ofverapamil. There were no episodes of third-degree block andno patient required cardiac pacing. Since verapamil can resultin a negative inotropic effect as well as a vasodilator effect, weexamined its effects on left ventricular ejection fraction andcardiac index as measured by two-dimensional echocardiogra-phy. The mean ejection fraction and cardiac index, however,remained within the normal range at 24 and 120 h during theverapamil infusion, 52.7 ±5% and 42.6 liter/min/m2 and 51.8±5% and 3.9 ±5 liter/min/m2, respectively. More importantly,

this normal cardiac data was demonstrated in patients attainingtwice as high steady state verapamil levels than previouslyreported in children. The two treatment courses which resulted

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VERAPAMIL-, VP-16-, VINBLASTINE-RELAPSED PEDIATRIC TUMORS

in significant negative inotropic toxicity were associated withmarkedly elevated levels of verapami 1 at 24 hours (1233 and1263 ng/ml) and at 120 hours (933 and 870 ng/ml) (Table 3).Similar cardiac toxicity has been seen in four of eight adultstreated with verapamil infusions of 0.009 mg/kg/min resultingin steady state levels of 1273 ng/ml (25). Both of our patientswith verapamil-induced cardiac toxicity responded to inotropicsupport, either dopamine or dobutamine. Their cardiac functionreturned to a normal baseline following the end of the verapamilinfusion.

Ozols et al. (25) have treated adults with continuous verapamil infusions in an attempt to overcome drug resistance inrefractory patients with ovarian carcinoma. He administeredAdriamycin 50 mg/m2 over 24 h simultaneously with continu

ous-infusion verapamil. He administered verapamil at threedifferent continuous infusion levels, 0.005 mg, 0.010 mg, and0.015 mg/kg/min until heart block or significant hypotensionoccurred. He then selected the maximal-tolerated dose for eachpatient. The mean tolerated dose (0.009 mg/kg/min) resultedin 50% significant cardiac toxicity. Since our dose was only55% of their mean-tolerated dose, we experienced significantly

less cardiotoxicity.Eight of our 11 treatment courses were given to children with

relapsed leukemia. Subsequently we experienced a 36% incidence of grade IV hematological toxicity. There were, however,only two episodes of bacterial sepsis, both of which respondedto broad spectrum antibiotics. We had no evidence of anyhepatic, renal, GI, or neurotoxicity during this study. Althoughclinical responses were not the objective of this clinical study,we noted eight of 11 partial responses, most of which resultedin cytoreduction of peripheral blasts, however, one M2-A bonemarrow was achieved in a relapsed patient with AML.

In summary this study attempted to optimize the previous invitro experience of modulating multiple-drug resistance by in

hibiting drug efflux and thereby increasing intracellular concentrations of cytotoxic agents. This protocol was designed toachieve plasma levels of verapamil previously demonstrated toaugment the cytotoxicity of vinblastine and VP-16. Our pediatrie study suggests that verapamil levels between 400 and500 ng/ml can be achieved with continuous infusion verapamilwith acceptable cardiac toxicity. The levels of verapamil reported in this study have previously been shown in vitro toaugment cytotoxicity of vinblastine and VP-16 in resistant andnonresistant human tumor cell lines.

The pharmacokinetics of continuous infusion verapamil havebeen described to be quite variable in children and periodicmonitoring of verapamil levels is required during this type oftherapy. Cardiac toxicity can be expected to be encounteredduring high steady state of verapamil. High verapamil levelsshould be suspected when clinical cardiac toxicity arises. Verapamil infusions should be promptly lowered or discontinueduntil levels are <500 ng/ml. Further clinical studies are neededto determine the maximal-tolerated dose of continuous infusionverapamil in children and then a phase II study is needed toexamine its efficacy in selected relapsed patients. The responsesof future phase II and III studies should be correlated to thepresence or absence of the MDR genotype and/or phenotypeat the beginning of therapy in refractory pediatrie cancer patients. The future use, however, of less cardiotoxic biologicalresponse modifiers, might enhance our ability to circumventthe development of multiple-drug resistance and achieve a

higher number or prolonged sustained complete remissionswith multiagent chemotherapy.

ACKNOWLEDGMENTS

The authors would like to thank William Krivit for his encouragement and support of this project. Additionally we would like to acknowledge the cooperation and expertise of the nurses in the pediatrieintensive care unit and excellent editorial assistance of Nancy Franks.

REFERENCES

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1989;49:1063-1066. Cancer Res   Mitchell S. Cairo, Stuart Siegel, Nick Anas, et al.   Pediatric TumorsVinblastine, and Continuous Infusion VP-16 in Drug-resistant Clinical Trial of Continuous Infusion Verapamil, Bolus

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