[CANCER RESEARCH 43, 5022-5025, October 1983]

Phase I Trial of Intravenous L-Phenylalanine Mustard plus the SensitizerMisonidazole1

C. Norman Coleman,2 Michael K. Friedman, Charlotte Jacobs, Joanne Halsey, Robert Ignoffo, Stephen Leibel,

V. Kate Hirst, Melanie Gribble, Steven K. Carter, and Theodore L. Phillips

Stanford University Medical Center, Stanford, California 94305 [C. N. C., C. J., J. H., V. K. H.]\ University of California San Francisco, San Francisco, California 94143[M. K. F., R. I., S. L, T. L P.]; and the Northern California Oncology Group, Palo Alto, California 94304 [M. G., S. K. C.]

ABSTRACT

Misonidazole (MISO), a hypoxic cell radiosensitizer, has beenshown in vivo to enhance tumor cell killing by melphalan (LPAM)with little or no enhancement of normal tissue injury. A Phase Itrial was conducted using MISO p.o. 2 hr before i.v. LPAM. Thehighest doses used were the single maximum tolerated dosesof MISO, 4 g/sq m, and LPAM, 0.6 mg/kg. Thirty-five patientswere entered; 30 were évaluablefor assessment of hematolog-ical toxicity, which was predicted to be the dose-limiting toxicity.

The median age was 60 years (range, 28 to 72 years). Mild tomoderate nausea and vomiting occurred in 80% of patients. Fivedeveloped serious hematological toxicity defined as nadir whiteblood cell count < 1000/cu mm, platelets < 20,000/cu mm or 4-

week posttreatment white blood cell count < 2000/cu mm,platelets < 50,000/cu mm. Four of the toxicities occurred at theLPAM dose of 0.6 mg/kg but were independent of MISO dose.One patient died of infection. Two patients whose tumor demonstrated an objective response to therapy and 10 others withdisease stabilization received additional courses. Four patientsdeveloped mild MISO neuropathy. Pharmacokinetic studies demonstrated that MISO did not appear to affect the pharmacoki-

netics of LPAM in plasma. Both LPAM and MISO can be givensafely at their individual maximum tolerated dose. This combination will proceed to Phase II trials.

INTRODUCTION

MISO3 is a 2-nitroimidazole introduced into clinical trials as a

sensitizer of hypoxic cells to radiotherapy (10, 18, 19, 26). Roseef al. (20) initially demonstrated that MISO can enhance tumorcell killing by chemotherapeutic agents in mice. This observation,corroborated by others, has been reviewed recently (17, 21).The sensitization occurs primarily with the bifunctional alkylatingagents with an ER of approximately 2.0 being observed by mostinvestigators (17). Some enhancement of normal tissue injurywas observed using single doses of MISO with the chemotherapy (ER, 1.0 to 1.6) in the mice. Since the normal tissue enhancement was less than the enhancement of tumor cell killing, atherapeutic gain was observed. At the time of initiation of thistrial, the animal data suggested that MISO was most effectiveas a sensitizer if given simultaneously with or shortly before thealkylating agent (7,16,17,20). The mechanism of this interaction

1Supported in part by Grants CA-05838, CA-25862, and CA-25827 from the

Division of Cancer Treatment, NIH, Department of Health and Human Services,Bethesda, Md.

2To whom requests for reprints should be addressed, at Division of Radiation

Therapy, Stanford University Medical Center, Stanford, Calif. 94305.3The abbreviations used are: MISO, misomdazole; ER, enhancement ratio;

LPAM, L-phenylalanine mustard; CBC, complete blood counts.Received April 5, 1983; accepted July 13, 1983.

had not been completely elucidated (3, 21, 24), but pharmaco-

kinetic interaction of the drugs had been postulated to be partof the mechanism in mice (21).

A Phase I trial using the combination of p.o. MISO plus LPAMwas initiated in August 1981. LPAM was chosen because in thelaboratory it appeared to be enhanced as well as any otheragent. Additionally, although it is an active drug, it is not used inmany first-line chemotherapy regimens and therefore will be a

new drug for many patients, even those previously treated withchemotherapy. The design of this trial is somewhat different thanthe standard Phase I trials in that the maximum tolerated singledose of MISO p.o. (26) and LPAM i.v. (2) were known. This studywas designed to see if MISO enhanced the hematological toxicityof LPAM or whether the full dose of both drugs could beadministered. We also studied the pharmacokinetics of LPAM tosee if MISO altered the plasma pharmacokinetics of LPAM ascompared to published data using LPAM i.v. alone (2).

MATERIALS AND METHODS

Patient Selection and Evaluation. All patients had histologically confirmed cancer refractory to conventional treatment or for which noeffective therapy was known. The patients had not received radiotherapyor chemotherapy during the 4 weeks prior to treatment (at least 6 weekselapsed since treatment with a nitrosourea or mitomycin C). All patientshad a life expectancy of at least 6 weeks, a Kamofsky performancescore of »50%, a WBC of &3500/cu mm, a platelet count of ss125,000/cu mm; bilirubin, <2.0 mg/dl; serum glutamiooxaloacetic transaminase<3 times normal; creatinine, <1.5 mg/dl. Informed consent was obtained

prior to treatment. Initial patient evaluation included complete history,physical examination, CBC with differential, platelet count, chemistry andelectrolyte panels, urinalysis, chest X-ray, and pertinent X-rays to help

evaluate tumor response. Patients were to have a weekly CBC aftertreatment and a complete réévaluationat 4 weeks. Retreatment withdrug could be given if the CBC and chemistries were still within theabove limits and if the treatment was deemed to be clinically indicatedby the patient's physician.

Drug Schedule and Administration. MISO and LPAM were obtainedfrom the Division of Cancer Treatment, National Cancer Institute, Bethesda, Md. MISO was supplied in 500- and 100-mg capsules. The

appropriate dose was administered p.o. 2 hr prior to LPAM infusion.LPAM, 100 mg/vial, was reconstituted by the addition of 1 ml of acidalcohol diluent followed by 9 ml of dipotassium phosphate-propylene

glycol diluent. Both diluents were provided by the manufacturer (Burroughs Wellcome, N. C.). The appropriate dose was added to 100 to200 ml of 5% dextrose in water solution U.S.P. and administered by i.v.infusion into a peripheral vein over 15 min. The initial dose of MISO was1.5 mg/sq m, and that of LPAM was 0.45 mg/kg. The schema is includedin Table 3. At least 3 fully évaluablepatients were entered on a givenstep. Dose escalation was done on a succeeding group of patients if thepreceding step was sufficiently nontoxic. The hematological toxicityscoring system used is shown in Table 1. Each patient was scored forhematological toxicity at their count nadir (2 weeks) and at recovery (4

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Phase / Trial of LPAM versus MISO

weeks). Additional patients were added to a step if: (a) any patientdevelopedGrade3 toxicity at Week 4; or (c) 3 patients developedGrade2 toxicity at week 4. The study was to be terminated if, on any step: (a)>50% of patients develop Grade 5 toxicity at any time; (b) >50% ofpatients develop Grade 4 toxicity at Week 4; (c) >75% of patientsdevelop Grade 3 toxicity at Week 4. To be évaluablefor toxicity andresponse, a patient must have been observed for at least 4 weeksfollowing treatment.

Pharmacokinetic Studies: LPAM. Pharmacokinetic studies weredone on 8 patients using a modification of the methods of Chang ef al.(6) and Furner ef al. (13). Blood samples were obtained at 0 time (startof infusion), at 15 min (end of infusion), and at 20, 30, 40, 50, 60, 90,120, 180, and 240 min. Blood samples were obtained in 10-ml heparin-ized tubes. The plasma was separated immediatelyand frozen at -70°if not processed on the same day. The samples were maintainedat 4°

throughout processing. One ml of plasma was removed for assay oftotal LPAM. Two ml of 10% HCIO4were added to 1 ml of plasma,whichwas then mixed vigorously on a vortex mixer and centrifuged at 1200 xg. One-half ml of KH2PO4was added to 1 ml of supernatant, mixedvigorously, and centrifuged. The supernatant was analyzed for LPAM.

Non-protein-boundLPAM was measuredin the plasma ultrafiltrates afterthree 0.5-ml aliquots of plasma were serially centrifuged through pre-soaked CF25 filter cones (Amicon, Lexington, Mass.) Urine for totalLPAM was processed similarly to plasma. LPAM was measured on aWaters high-pressure liquid Chromatograph,using a 25-cm C,e-nBon-dapak column, with a mobile phase of 52% methanol-1% acetic acid at1.6 mi/min. Dansyl prolene (Sigma Chemical Co., St. Louis, Mo.) wasused as an internal standard.

MISO was measuredas previously described (27).Analysisof plasmaconcentration versus time data was carried out using the NIH ProphetComputer System (14). Because the data showed biexponential disappearance when plotted on semilogarithmic graph paper, a 2-compart-ment pharmacokineticmodel was used to fit the data points.

Tumor Response. Tumor response for patients with measurablelesions was judged as follows using the following 6 categories of response, as is used by the Northern CaliforniaOncology Group: Category1, complete response; Category 2, equivocal evidence of diseases;Category 3, partial response (reduction by at least 50% of the productof the 2 longest perpendicular diameters); Category 4, minor response(reductionby less than 50% of the product of the 2 longest perpendiculardiameters);Category 5, stable disease; Category 6, progression.

Tabte!ToxicityscoreScore

WBCfxIO'/cumm)0

>3.51 3.0-3.52 2.0-2.93 1.0-1.94 0.5-0.95 <0.5Table

2Patientpopulation (n = 35)

Medianage, 60 years (range, 28 to72).SexMale

FemalePrimarycancer site

ColonLungHead and neckMelanomaSarcomaOvaryBreastPancreasIslet cellRenalcellCervix

Prior treatment withChemotherapyChemotherapy includingalkylating agentsRadiotherapyNo prior treatmentDrug

dosePlatelet

(xio^cumm)>100

75-10050-7420-4910-19

<10No.19

169

563332111

131

10241Phase/:RESULTSThirty-five

patients were entered onto this study; 5 wereinevaluable due to early deaths or insufficient follow-up data.

One patient, inadvertently given 100 mg of LPAM, died of rapidlyprogressive disease 4 days after drug administration. The characteristics of the patients are in Table2.The

dose of drugs, numbers of patients, and hematologicaltoxicity are illustrated in Table 3. Severe toxicity, as judged by ahematological score of 4 or 5 occurred in Steps 2, 3, and 5.Overall, 5 patients had this level of toxicity. In Steps 2, 3, and5,4

of the 5 patients with the nadir toxicity are the samepatientswhohad the minor toxicity at 4 weeks. Overall, 7 patients had

major or minor toxicity. The one drug-related death (Step 5)

occurred in a patient with prior chest wall radiotherapy and 15months of prior chemotherapy. It can be seen that for all patientsgiven LPAM, 0.6 mg/kg, the toxicity did not appear to increasewith an increasing dose of MISO. With small numbers of patients,it is possible that an effect of MISO dose on LPAM toxicity couldbe missed. Assuming an overall toxicity incidence of 16% (5 of30), if the strongest trend of increasing toxicity with MISO dosewas present (i.e., 0% in the lower-dose MISO group and 30% in

the highest dose MISO group), the maximal type 2 error wouldbe 25%.

The average length of prior chemotherapy was 7 months. Fourof the 5 patients with Grade 4 or 5 toxicity had over 1 year ofchemotherapy; 2 of them also had receivedradiotherapy.Tables

LPAMplus MISOToxicity

scoreatNo.

évalua- 4-wk Total no. ofNo. évaluable ble at Nadir 4-wk minor patients

LPAM MISO No. of pa- at both nadir either nadir Ineval- score score score with majorStep (mg/kg) (g/sqm) tients and 4 wk or 4 wk uabte 4or5 4or5 2or3toxicity81

0.45 1.52 0.45 2.03 0.60 2.04 0.60 3.05 0.60 4.06

37 49 64 49835

252

100000 3101 13 020220 000200120225

5 5 0 f 58Toxicity required for "stopping" as outlined in "Materials and Methods."6 Four of these 7 patients were the same patients who had nadir toxicity.

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C. N. Coleman et al.

Table 4

Pharmacokinetic parameters

DoseMISO

(g/sqm)2.0

2.03.04.0LPAM(mg/kg)0.45

0.600.600.60No.

observed82

114Peak

levelUg/ml)2.0

2.41.72.5Total

LPAMVDss

(liters)31

202722fW

(min)53

469268Clearance

(liters/min)0.36

0.330.270.37No.

observed1

113Unbound

LPAMPeak

level(^g/ml)0.28

0.420.210.36VDss

(liters)112

9388

105M(min)14

271629Clearance

(liters/min)4.5

2.53.32.8

All patients2.3 ±0.6* 22 ±7 65 ±30 0.34 ±0.08 0.33 ±0.08 101 ±27 24 ±8 3.1 ±1.0

Table 5

TherapeuticresponseResponseProgression

StabilizationResponse

<50%Response >50%Early deathsNo.

ofpatients17151

11No.

receiving multiplecourses0

2 courses, 83 courses, 25 courses, 12 courses, 1

" Number observed, number of patients in whom analysis was done; peak level, plasma level obtained at end of LPAM infusion; VDss, volume of distribution, steady

state.Mean ±S.D.

MISO produces a peripheral neuropathy in approximately 30to 50% of patients given a total dose of 10.5 to 12 g/sq m (10,18, 26). A minor neuropathy will be detectable but will not bebothersome to most patients. A moderate neuropathy can bedebilitating; therefore, if any patients had any symptoms suggesting neuropathy, the MISO was discontinued. A minor toxicitywhich was subjective only was encountered in 4 patients atdoses of 2.0 to 8.0 g/sq m. One patient given 2 g/sq m developedminimal parasthesias; one given 3 g/sq m complained of numbness of the fingers but received an additional cycle of drugswithout problems; a patient given 4 g/sq m complained ofunilateral foot numbness; and the patient at 8 g/sq m developedwhat was felt to be a typical MISO-induced parasthesia of the

feet.Nausea and vomiting occurred in 80% of patients. It was with

equal frequency on all steps and was generally of less than 12hr duration. Two patients developed a drug rash and had thetreatment discontinued. No other organ toxicity was encountered.

Pharmacokinetics. The results of the pharmacokinetic analysis are shown in Table 4. Since the percentage of unboundmelphalan is relatively small (10 to 20%) and the half-life is short,

few patients had measurable values beyond 50 min. There weresufficient data to analyze free melphalan in 6 of the 8 patients.

The steady state volume of distribution was larger for unboundLPAM (101 liters) compared to that for total LPAM (22 liters).The unbound drug had a shorter terminal half-life of 24 min

compound to 65 min for total LPAM. These data for total LPAMare similar to those reported by Alberts ef al. (2), who reporteda half-life of 108 ±21 (S.D.) min. However, the effect of MISO

on plasma pharmacokinetics of LPAM will be further evaluatedas part of a randomized Phase II trial using LPAM with andwithout MISO.

Therapeutic Responses. Thirty-three of the 35 patients had

measurable disease. Table 5 lists the therapeutic response andsurvival. Two patients had an objective response, one withmelanoma and the second with adenocarcinoma of the lung.

DISCUSSION

Melphalan has been useful clinically for multiple myeloma,lymphoma, ovarian cancer, and breast cancer (12). It has beenadministered in higher doses to patients with melanoma usingisolated limb perfusion (15). These studies suggest that a higherdose may be more effective therapeutically than standard dosesof drug. In this study, LPAM was administered i.v. because (a)absorption can be erratic after p.o. drug (1) and (b) time of peakdrug level could be best controlled. The starting dose was 75%that of the maximum i.v. dose used by Alberts ef al. (2). The

purpose of the study was to see if MISO modified the hemato-

logical toxicity of LPAM and to see if MISO altered the pharmacokinetics of LPAM, as compared to previously published results(2). MISO has now been used as a radiosensitizer in manypatients (18). It is well absorbed p.o. and has a maximumtolerated single dose of 4 g/sq m (26). MISO was started at arelatively low single dose, 1.5 g/sq m.

The initial animal data (7,16,17,20) suggested that the MISOshould be given simultaneously with, or slightly before, thealkylating agent. A 2-hr interval was chosen, because this is the

time required for MISO to approach its peak plasma level afterp.o. administration (26). Subsequently, it has been shown in micethat maintaining a sustained level of sensitizer which simulatesthe drug half-life after p.o. dose in humans (13 hr) produces a

superior therapeutic index compared to a single pulse of drug(4). In mice, the sustained level produces no enhancement ofnormal tissue injury while an ER of 1.8 to 2.2 was obtained fortumors. In animal studies, a large dose range of alkylating agentswas used. In support of the use of this combination in humansare animal data showing that the ER was either constant overthe dose range of alkylating agent used or a higher ER was seenat the lower doses of alkylating agent (3,16,17). Thus, studiesin mice in which human MISO pharmacokinetics was mimickedand clinically achievable LPAM doses were used have producedan ER of approximately 2 for tumors, with no enhancement ofnormal tissue damage.

The results from this trial demonstrate that LPAM i.v. can begiven at full dose (0.6 mg/kg) and MISO can be used at its single-

dose maximum tolerated dose (4 g/sq m) without causing excesshematological toxicity. Few patients developed severe hemato-

logical toxicity (Grade 4 or 5) at any time during their treatment.Drug treatment was repeated in 12 patients, 2 of whom had ameasurable tumor response. Nausea and vomiting were the mostfrequent toxicities and were generally mild and limited to a fewhr. It occurred at all dose levels. Four patients developed mildperipheral sensory neuropathy. It would be expected that morepatients would develop it had they received more drug. Theincidence of peripheral neuropathy is approximately 30 to 50%of a total MISO dose of 10.5 to 12.0 g/sq m (18, 26). It is

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Phase l Trial of LPAM versus MISO

conceivable that administering MISO on an every-4-week sched

ule may decrease its toxicity, but it is unlikely that a substantialreduction will be obtained. Therefore, if the 2-nitroimidazole

drugs are effective as chemosensitizers, a less toxic drug wouldbe needed. Desmethylmisonidazole, the second of those compounds to enter clinical trial, was somewhat less neurotoxic (8)but not sufficiently so to proceed beyond the Phase I study. Anewer drug, SR-2508, which may be one-sixth as neurotoxic as

MISO has entered Phase I clinical trials as a radiosensitizer. Itappears that it is equally effective in vivo as a sensitizer as MISOwhen used with alkylating agents (4, 16).4 It is likely that it will

be tried as a chemosensitizer in clinical trials in the future.The mechanism of chemosensitization has not been fully elu

cidated (3, 17, 21, 24). Since one possible mechanism was apharmacokinetic interaction of MISO with LPAM, we examinedthe pharmacokinetics in some of these patients. The tv,ßvaluesfor total LPAM in our study (65 ±30 min) are similar to thatpreviously obtained by Alberts ef a/. (108 ±21 min) for patientstreated with i.v. LPAM (2), although our assay methods differedslightly. Thus, if a pharmacokinetic interaction exists, it is probably at most a minor effect. This will be further investigated aspart of a randomized Phase II trial using LPAM, with or withoutMISO. Animal data indicated that single-dose MISO alters the

pharmacokinetics of LPAM in part by reducing the body temperature of the mice (3, 17, 25). However, little alteration in pharmacokinetics was seen4 using multiple doses of MISO in a

manner that mimics the plasma profiles in humans. More likely,mechanisms of chemosensitization include an increase in LPAM-

induced DMA strand breaks by MISO or partial depletion ofintracellular glutathione in hypoxic cells by MISO (24).

This trial has demonstrated that LPAM and MISO can beadministered at their maximum tolerated doses with little serioushematological toxicity. Phase II trials are to be initiated with thiscombination through the Northern California Oncology Group.One will be a randomized Phase II trial for patients with advancednon-oat cell lung cancer, and the other will be single-arm Phase

II trials for patients with malignant melanoma. They will use MISOat 4 g/sq m 4 hr prior to LPAM, an interval that appears optimalin vivo.5 Care will be taken after exceeding a total MISO dose of

8 g/sq m due to the possible development of neuropathy. Theindividual dose of MISO per treatment will be reduced to 2 g/sqm beyond that point. Since a higher plasma level of sensitizerprovides better sensitizaron,5 it will be advantageous to have adrug less toxic than MISO. SR-2508, now being evaluated in a

Phase I trial as a radiosensitizer, may be such a drug (5).Additional chemotherapeutic agents that may be sensitized byMISO include cyclophosphamide and 1-(2-chloroethyl-3-cyclo-hexyl-1 -nitrosourea (17), and they are worthy of clinical trials.

ACKNOWLEDGMENTS

The authors wish to thank Dr. Terrence Blaschke for assistance with analysisof the pharmacokinetic data, Dr. Byron Brown for assistance with statisticalanalysis. Marge Keskin for secretarial assistance, and Linda Rich, R.N., for assistance with the care of the patients.

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1983;43:5022-5025. Cancer Res   C. Norman Coleman, Michael K. Friedman, Charlotte Jacobs, et al.   Sensitizer MisonidazolePhase I Trial of Intravenous l-Phenylalanine Mustard plus the

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