ICANCERRESEARCH54,2636-2642,May15,19941

Very few agents show activity against NSCLC.3 Only five drugsappear to have moderate activity against NSCLC: cisplatin, ifosfamide, mitomycin C, vindesine, and vinblastine (1, 2). Since theintroduction of cisplatin-based chemotherapy, there are data showingthat a variety of combination chemotherapy regimens such as cisplatinplus Vinca alkaloid (vindesine/vinbiastine) or etoposide and mitomycin C plus Vinca alkaloid plus cisplatin produces a response inNSCLC in the range of 25—50%(3, 4). A recent randomized studyshowed that cisplatin-based combination chemotherapy produces aslight but significant improvement in survival (5, 6). However, theoverall outcome for patients with advanced NSCLC remains poor(7—10).Clinical trials on NSCLC have been made difficult by the lackof effective drugs. Advances in treatment of this disease will be madeonly by discovering more active agents and successfully includingsuch drugs in rational combination chemotherapy regimens.

CPT, obtained from the Chinese tree Camptotheca accuminata, isan alkaloid with a novel ring structure (1 1). Although CPT has shownpromising antitumor activity in vitro (12, 13) and in vivo, its clinicalactivity was disappointing because of its low therapeutic efficacy andsevere toxicity to the intestine, bladder, and bone marrow (14—17).Toimprove the therapeutic index of CPT, various derivatives of CPThave been semisynthesized, including CPT-11, a new water-solublederivative, which has potent antitumor activity against several tumorsin the munne system (18). SN-38, a metabolite of CVF-11, showsmuch stronger cytotoxicity than CPT-11 in vitro (19), and bothCPT-11 and SN-38 may be responsible for the antitumor effect andside effects. A phase I clinical study of CPT-11 by single-dose i.v.administration every 4 weeks showed that the DLT of CPT-11 wasmyelosuppression and the MTD was 250 mg/m2 (20). Camptothecinand its derivatives have demonstrated schedule-dependent antitumoractivity and toxicity (15, 21). A phase I study of CPT-11 on a scheduleof i.v. administrationonce weekly revealedthat the MTD on thisschedule was 100 mg/m2 and the DLTs were myelosuppression (predominantly leukopenia), nausea and vomiting, and diarrhea (22). Thisschedule appears to allow a CPT-11 dose intensity which is double thedose intensity possible on a once-every-4-weeks schedule. The response rate of CPT-11 in patients with advanced NSCLC withoutprior chemotherapy has been reported to be 32% with i.v. administration on a schedule of 100 mg/m2 weekly (23).

Cisplatin and vindesine are active as a single agent against NSCLC(1, 2). The combination of cisplatin and Vinca alkaloid currently isone of the active regimens for patients with advanced NSCLC (24—

3 The abbreviations used are: NSCLC, non-small cell lung cancer; CPT, camptothecin;

CPT-11, irinotecan, 7-ethyl-10-[4-(1-pipeodino)-1-pipetidino]carbonyloxy-camptothecin;SN-38, 7-ethyl-10-hythoxy-camptothecin;MiD, maximumtolerateddose; DLT, dose-limiting toxicity; C max, maximum concentration in pissma AUC, the area under the plasmaconcentration versus time curve; G-cSF, granulocyte colony-stimulatingfactor-,GM-@3F,granulocyte-macrophagecolony-stimulatingfactor.

Irinotecan hydrochloride (CPT-11), a semisynthetic derivative of camptothecin, has been demonstrated to be active against solid tumors such asnon-small cell lung cancer and colorectal cancer. Two combhaationphaseI trials were undertaken to determine the maximum tolerated dose ofCPT-11 in combination with cisplatin and vindesine in patients with

advanced non-small cell lung cancer. All 46 patients (age 32—73years)entered hato these trials had a good performance status (Eastern Cooperative Oncology Group score, 0—1)and had received no prior chemother

apy or radiotherapy. In the first trial, 14 stage IV and 2 stage RIb patientswere studied; ha the second trial 30 patients with stage IV disease wereaccrued. In the first trial, CPT-11 was given as a 90-mm i.v. infusion ondays 1 and 8 in combination with a fixed dose ofcisplatin (100 mg/rn2, Lv.,on day 1) and vindesine (3 mg/m2,Lv.,on days 1 and 8), every 4 weeks. Thestarting dose of CFI@-11was 25 mg/m2, and the dose was increased haIncrements of 25 mg/m2. In the second trial, the doses of either CPT-11(days 1 and 8) or cisplatin (day 1) were escalated with a fixed dose ofvindesine (same dose as the first study) given ha a 4-week cycle. Thestarting doses ofCFI@-11and cisplatin were 20 and 60 mg/m2, respectively,and the dose of either CPT-11 or cisplatin was hacreasedIn increments of20mg/m2.Atleast3patientswereenteredateachdoselevelhabothtrials.Use of granulocyte colony-stimulating factor or granulocyte-macrophagecolony-stimulating factor was not permitted ha this trial. In the first trial,grade 4 granulocytopenIa and grade 3 diarrhea were dose limiting at 50mg/m2 CPT-11, which represented the maximum tolerated dose. At thesubsequent dose of CPT-11, 7 new patients were requited at the 50%reduced dose level of 37.5 mg/m2 on days 1 and 8. Nine patients were

evaluable for response, and 4 ofthem achieved a partial response. In spiteof a low dose of CPT-11 (25—37.5mg/rn2),the maximum concentration haplasma ofCPT-l1 (>0.4pg/ml) reached >10-fold the in vitroconcentrationof CPT-l1 required for 50% inhibition of growth. In the second trial, thedose-limiting toxicities were grade 4 granulocytopenia lasting for 7 daysand grade 3 diarrhea. The maximum tolerated dose was 100 mgfm2ofCFF-11 and 60 mg/m2 of cisplatin In this regimen. The other severetoxicity was to the liver. Ten of 30 patients entered (10 of 22 patientsassessable for response) achieved a partial response. Intractable diarrheainduced by CPT-11 was associated with the dose of cisplatin used In ourtrials and occurred cohacidentally with granulocytopenia of grade 4. Forfuture phase H trials, we recommend doses of CPT-11 of 37.5 and SOmg/rn2 on days 1 and S combined with vindesine and either high-dosecisplatin (100 mg/m2) or low-dose cisplatin (60 mg/m2), respectively.

Received 11/18/93; accepted 3/21/94.The costs of publication of this article were defrayed in part by the payment of page

charges. This article must therefore be hereby marked advertisement in accordance with18 U.S.C. Section 1734 solely to indicate this fact.

I This work was supported in part by Grants-in-Aid for Cancer Research and by the

Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health andWelfare.

2 To whom requests for reprints should be addressed.

2636

Phase I Clinical Trial of Irinotecan (CPT-11), 7-Ethyl-1O-[441-piperidino).-1-

piperidino]carbonyloxy-camptothecin, and Cisplatin in Combination withFixed Dose of Vindesine in Advanced Non-Small Cell Lung Cancer'

Tetsu Shinkai,2 Hitoshi Arioka, Hiroshi Kunikane, Kenji Eguchi, Yasutsuna Sasaki, Tomohide Tamura,Yuichiro Ohe, Fumihiro Oshita, Makoto Nishlo, Atsuya Karato, Hiroaki Okamoto, Hi@jime Nakashinia,

Hironobu Ohmatsu, Junichi Shiraishi, Naohiro Nomura, and Nagahiro SaLjo

Department of Internal Medicine, National Cancer Center Hospital fT. S., H. A., H. K, K K, Y. S., T. T., V. 0., F. 0., M. N., A. K, H. 0., H. N., H. 0., J. S., N. N., N. S.],Pharmacology Division, National Cancer Center Research Institute (N. S.] 1-1, Tsukiji 5-c/tome, Chuo-ku, Tokyo 104, Japan

ABSTRACT INTRODUCTION

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First trialSecondtrialTotalPatients

entered16a31346Age:median(range)(yr)56 (42—73)56(32—71)56(32—73)Sex:

male/female8/821/929/17Performancestatus(Eastern

Cooperative OncologyGroup)04481122638HistologyAdenocarcinoma142842Squamous

cellcarcinoma123Largecellcarcinoma101StageHIb202IV143044Prior

therapyNone162440Surgery066a

u@im@otherwisespecified,resultsarenumbersof patients.

Table 2 TOxicityoffirstphase ItrialDose

(mg/rn2)

CFr-ii CisplatinNo.

of patients/no. of cycles/no. of patients

WIthDLTCommon

toxicity2WBC

(grade)

34Granulocyte

(pade)

2 3 4 2Platelet

(grade)

34Diarrhea

(grade)

2 3Nausea/

vomiting(grade)

2 3Liver

(grade)

2 3Kidney

(grade)

225

10037.5 10050 100

aNumbersin parenth6/11,2

7/13123/3/3

eses, numbers of patie0

40

nts w3

22

ith grade2

11

4 gran1

0 4(i)a 00 2 5(1) 10 1 2(1) 0

ulocytopenia lasting 7 days.0

000

002

23 10 34

25 12 10

00 10 00

00

PHASE I STUDY OF CPT-11, CISPLATIN, AND VINDE5INE iN NSCLC

Table 1 Patient characteristics stating that the patient was aware of the investigational nature of this treatmentregimen. Pretreatment evaluation included medical history, physical examination, complete blood count, bone marrow examination, serum biochemicalanalyses, chest roentgenogram, electrocardiogram, and urinalysis. All patientsunderwentradionucidebone scan,computerizedtomographyof the brainandthorax, and ultrasonography or computerized tomography of the abdomen. Allpatients were admitted to the National Cancer Center Hospital during this trial.Complete blood count, biochemical tests, serum electrolytes, urinalysis, and

chest roentgenograms were obtained weekly during this phase I trial. Tests ofmeasurable disease parameters such as computerized tomography were repeated every 4 weeks. The patient characteristics are shown in Table i.

Study Design and Treatment Plan. All patientswere hospitalizedfor thecombined treatment with CPT-11 plus vindesine plus cisplatin.

In the firststudy,the startingCPT-11dose was 25 mg/rn2on days I and8(50 mg/m2/course), and the dosage was increased in subsequent incrementsof 25 mg/rn2. The starting dose (50 mg/m2/course) was based on 1/10(26.4 mg/rn2)of the dose which was lethal to 10% of the mice tested or 1/3(69.3 mg/rn2)ofthe low toxic dose in the dog on the single-dose schedule (dataon file at Daiichi Pharmaceutical Co., Ltd., and Yakult Honsha Co., Ltd.).CPT-1i was kindly provided by Yakult Honsha (Tokyo, Japan), and Daiichi(Tokyo, Japan). Six patients were entered at the first level, seven patients wereentered at the second level, and three patients were entered at the third level(Table 2). The dose of CPT-11 in 500 ml of normal saline or 5% glucose wasinfused i.v. over 90 min. Vindesine was given at a dose of 3 mg/rn2 as an i.v.

bolus on days 1 and 8. Cisplatin was given i.v. at a dose of 100 mg/rn2over30 mm after prehydration with 500 ml of normal saline following CPT-11administration on day 1. Following administration of cisplatin, patients received mannitol (20%) i.v. at a rate of 50 mI/h over 6 h and 2000 ml of 5%glucose in 0.45% NaCI with 20 mEq K@/liter at a rate of 200 mI/h. To con

trol cisplatin-induced emesis, patients received high-dose metoclopramide(2 mg/kg, i.v., every 2 h X 4) plus i.v. infusions of dexamethasone and

promethazine.The course was repeatedevery 4 weeks.In the second trial, a successive cohort of new patients with metastatic

NSCLC was used to study interpatient dose escalation of CPT-11 (i.v. on days1 and 8) and cisplatin (iv. on day 1) with a fixed dose of vindesine (3 mg/rn2,i.v., on days 1 and 8), given every 4 weeks (if possible every 3 weeks). Thestarting doses of CPT-11 and cisplatin were 20 and 60 mg/rn2, respectively,and the dosage was escalated in subsequent alternate increments of 20 mg/rn2.The starting dose of CPT-11 in the second trial was lower than that of the firsttrial. We chose 20 mg/rn2 as the starting dose of CPT-11 to ensure safety,because two of six patients entered at the first dose level (25 mg/rn2 CPT-11on days 1 and 8) in the first phase I trialexperienceddose-limitingtoxicity.The goal was to focus primarily on the dose escalation of CPT-11. Weattempted to escalate the dose of cisplatin to 80 mg/rn2. The planned doselevels of CP'I'-ll/cisplatin were 20/60, 40/60, 60/60, 60/80, 80/60, 80/80, and100/80 mg/rn2.The hydration, rnannitol-induceddiuresis, and antierneticswereadministered in the same way as in the first study.

We initiallyplannedto treatthreepatientsat each dose level. If one or twoof the three patients at a given dose experienced any of the toxicities used todefine the MTD, threeadditionalpatientswere treatedat the dose level. Nodose escalationwas acceptedin the same patient.An MiD was regardedasone thatproducedany of the following in at least 50%of the patientstreatedat a given dose level: (a) nonhematological toxicity of grade 3 or nausea andvomitingofgrade 4; (b) thepersistenceofa nadirwith anabsolutegranulocytecount of <500/mm3or a platelet count of <50,000/mm3for 7 days. This wasdeterminedby checkingcomplete blood counts every otherday when leuko

26) and has been shown to prolong survival significantly comparedwith the best supportive care of patients with advanced NSCLC (5)and compared with radiation alone in patients with stage III NSCLC(6). In order to reinforcethe therapeuticefficacy of this combinationagainst advanced NSCLC, various agents have been combined withcisplatin and Vinca alkaloid (9, 27—29).However, there are no clearsurvival data to support the idea that a regimen using more than threedrugs is superior to a regimen using two drugs.

CPT-1 1 appears to be one of the most promising novel anticanceragents (30). In preclinical studies, CVF showed no cross-resistancewith cisplatin (31—33).To evaluate the potential therapeutic benefit ofadding CPT-1 1 to vindesine plus cisplatin and to further assess thetoxicity of CPT-11 in combination chemotherapy, we performed twophase I clinical studies in patients with metastatic NSCLC who hadreceived no prior chemotherapy or radiotherapy. The purposes ofthese studies were (a) to determine the optimal doses of CPT-11 andcisplatin in combination with a fixed dose of vindesine, (b) to furtherassess the toxicity of CPT-11 in combination chemotherapy, and (c)to study the clinical pharmacologyof CPT-11 and its metabolite,SN-38.

MATERIALS AND METhODS

Patient Population. Patients with histologically or cytologically confirmedadvancedNSCLCwere eligible for this phaseI trial.None of the patientshadreceivedpriorchemotherapyor radiotherapy.Othereligibilitycriteriaincludedexpected survival of 6 weeks, age <75 years, Eastern Cooperative OncologyGroup performance score of 0—1,measurable lesions, no brain metastasis,adequate hematological function (WBC 4000/mm3, platelet count100,000/mm3, hemoglobin 11 g/dl), renal function (serum creatinine@ 1.5mg/dl, creatinine clearance >60 mI/mm), and hepatic function (total serumbilirubin < 1.5 mg/dl, glutamic oxaloacetic transaminase and glutamic pyruvictransaminase less than twice the normal range, indocyanine green test 15%).The protocolsused were approvedby the ethical committeeof the NationalCancer Center (Tokyo). Written informed consent was obtained in every case

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Dose (mg/m2)

CFT-11 CisplatinTotalno.

patientsNo.

ofcycles/patient

[median(range)@CRPRSDPDNA2510063(1—5)0320137310072

(1—3)024015010031(1—1)00003

PHASE I STUDY OF CFr-11, CISPLATIN, AND VINDESINE IN NSCLC

cyte and platelet counts decreased <2,000/mm3 and 50,000/rnrn3, respectively.

The reason we decided to use granulocytopenia lasting 7 days as a doselimiting factor is that we forecasted that this regimen would induce severegranulocytopenia and granulocytopenia would be manageable under the careful supervision provided by the hospital setting. Use of G-CSF or GM-CSFwas not permitted in this trial. In addition, no prophylactic measures such asantibiotics were undertaken prior to occurrence of fever associated withgranulocytopenia.

Toxicity was graded according to the common toxicity criteria (34). Patientswere treated for at least two cycles of therapy unless disease progression orunacceptable toxicity was encountered or the patient's wishes intervened. Nodosage rnodification was made on the basis of bone marrow toxicity. In thecase of stable or progressive disease after two courses of treatrnent, subsequenttherapy was left to the discretion of the physician in charge of the patient. Thecriteria for response were as follows. Complete response was defmed as thecomplete disappearance of all evidence of turnor for at least 4 weeks. Partialresponse was defined as a >50% reduction in the sum of the product of the twogreatest perpendicular diameters of all indicator lesions for at least 4 weeks andno appearance of new lesions or progression of any lesion. Disease progressionwas defined as a 25% increase in tumor area or the appearance of newlesions. All other circumstances were classified as stable disease.

Pharmacokinetics. In the first study the pharmacokinetics of CPT-11 andSN-38 were determined for the first three cohorts of patients treated at eachdose level. CPT-11 was infused over a 90-mm period. Blood samples (5 ml)were drawn into heparinized tubes before infusion; then at 30, 60, and 90 (endof CPT-11 infusion) mm; and 5, 15, and 30 mm and 1, 2, 3, 4, 8, 12, and14 h after the end of the CPT-11 infusion. Samples (5 ml) were centrifugedimmediately at 4°C,and then plasma was stored at —40°Cuntil assayed. Apreviously described high-performance liquid chromatography technique (19)was used for CPT-1 1 and SN-38 rneasurernents in plasma. The pharmacokinetic analysis was performed using a nonlinear estimation program, PCNonline (Statistical Consultants mc, Lexington, KY). The AUC was calculated

by using the trapezoidal method; the portion of the AUC after the final timepoint was calculated by dividing the final detectable CPT-11 or SN-38 concentration by the terminal disposition rate constant (35).

RESULTS

Sixteen patients were enrolled in the first trial from January 1990 toJuly 1990 and received 33 courses of the CPT-1 1-cisplatin-vindesineregimen. Thirty patients were entered into the second trial from July1991 to April 1993 and received 68 courses of this regimen.

First Trial

Toxicity. The common toxicities (criterion grade 2) encounteredduring the first 8 weeks of treatment (first and second courses) in thefirst trial are summarized in Table 2. The dose-limiting toxicities onthis schedule were granulocytopenia and diarrhea. All three patientstreated at 50 mg/m2 CPT-11 (100% increment) developed grade 3(two patients) or 4 (one patient) diarrhea, and one of these threepatients experienced granulocytopenia of grade 4 lasting 10 days. Allthree patients at this dose level (50 mg/m2 CPT-1 1 on days 1 and 8)were removed from the study because of toxicity after one cycle oftreatment. The subsequent dose of CPT-11 was decreased to 37.5mg/m2@ days 1 and 8 (50% increment). At the CPT-11 dose of 37.5mg/m2, all seven patients experienced granulocytopenia of grade 3 or4. However, only one patient experienced granulocytopenia of grade4 lasting 7 days associated with diarrhea of grade 3. Medianduration of granulocytopenia of grade 4 was 4 days (range, 2—10days). However, leukopenia or granulocytopenia did not result in anytreatment delay at 25 or 37.5 mg/m2 CPT-11. No life-threateninginfections were observed as a result of granulocytopenia. Thrombocytopenia was generally mild, and only one patient at the CPT-11 doselevel of 37.5 mg/m2 experienced thrombocytopenia of grade 2. Anemia of grade 3 was observed in two of six patients and five of sevenpatients at the CPT-11 dose levels of 25 and 37.5 mg/m2, respectively.

Usually diarrhea was observed as frequent small amounts of caddyor watery stools from day 8 to day 16 after the start of treatment. Itoccurred coincidentally with granulocytopenia of grade 4. No patientsexperienced tarry stool or grossly bloody diarrhea. One patient receiving 50 mg/m2 CPT-11 who experienced diarrhea of grade 3 fromday 9 to day 19 was examined by colonoflberscope on day 22, aftertreatment. Macroscopic examination revealed mild erosion at severalpoints, and histological examination revealed colonic mucosa withsuperficial erosion. Another patient at the CPT-11 dose of 50 mg/rn2who experienced diarrhea of grade 3 from day 6 to day 12 wasexamined with barium enema on day 11 after the start of treatment.No remarkable change was observed except for diverticulosis. Grade3 elevation of transaminase occurred in one patient, but this mighthave been caused by vindesine because in this patient we observedsimilar evidence of liver dysfunction when vindesine and cisplatinwere administered without CPT-11 following the current treatment.No renal insufficiency of grade 2 was observed. The MTD in thefirst phase I trial was 50 mg/rn2 CPT-11 on days 1 and 8 combinedwith high-dose cisplatin (100 mg/rn2) and vindesine (Table 2).

Response to TreatmenL Table 3 shows the therapeutic responsein patients treated with this regimen in the first phase I trial. Fivepatients were nonassessable for response, because they were removedfrom the study after one cycle of treatment for the following reasons:one had diarrhea of grade 3 at the first level, one had liver dysfunctionof grade 3 at the second level, and three had diarrhea of grade 3and/or granulocytopenia of grade 4 lasting 7 days at the third level.Two patients with only diarrhea of grade 3 as the dose-limitingtoxicity received the second course of treatment and were successfullytreated without further dose-limiting toxicity.

No patient achieved a complete response. At the CPT-11 dose levelof 25 mg/rn2, three of five assessable patients achieved partial responses. At the CPT-11 dose level of 37.5 mg/rn2, two of six assessable patients achieved partial responses. At the CPT-11 dose level of50 mg/rn2, a >50% shrinkage of the tumor was observed in twopatients after one cycle of treatment. Overall, five of the 16 patientsentered (five of 11 assessable patients) achieved partial responses.

Second Trial

Toxicity, The toxicities of grade 2 observed during the first 8weeks of treatment in the second trial are summarized in Table 4.Before the start of the second trial, the planned dose levels of CPTli/cisplatin were 20/60, 40/60, 60/60, 60/80, 80/60, 80/80, and 100/80mg/rn2. However, as listed in Table 4, a 60/80-mg/rn2 dose level ofCPT-11/cisplatin was found to be intolerable. Therefore, subsequentdose escalation was modified. As also shown in Table 4, granulocytopenia of grade 4 was observed at each dose level; however, granulocytopenia of grade 4 lasting 7 days was observed at the 60/80-mg/rn2 dose level of CPT-11/cisplatin. The median duration ofgranulocytopenia of grade 4 was 3 days (range, 1- 10 days). Tenpatients experienced granulocytopenic fever of grade 2, and febrileneutropenia of grade 4 was observed in three patients. However, nopatient developed life-threatening infection. Thrombocytopenia was

Table 3 Therapeutic response in first phase I trial

No. of patientsresponding―

a CR, complete response; PR, partial response; SD, stable disease; PD, progressivedisease; NA, nonassessable.

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Table5 Granulocytopeniaand diarrhea in the secondphase ItrialDose

(mg/m2) of CPT-11/cisplatin20/6040/60&W60

60/80 80/60 100/60

3335115913782290/00/00/01/12/42/2

1221112—347712

(10—15)7(5-8)0/0

PHASE I STUDY OF C?F-11, CI5PLATIN, AND VINDESINE IN NSCLC

Table4 ToxicityofsecondphaseI trial

No. of patients with common toxicities

Nausea/vomiting

(grade)

2 3Liver

(grade)

2 3Kidney

(grade)

22

000020000200002200032010400 10

Dose(mg/rn2)No. of patients'no. of patientsWBC

(grade)Granulocytes (grade)Platelet (grade)Diarrhea(grade)CPT-11

CisplatinwithDLT23423 42342320

603/021001 20000040603/011102 10001060603/011110 20001060805/314000 5(1)―00002806011/325403 8(2)1003210060

aNumbersin parentheses,513numbersof patients11withgrade140granulocytopenia1

4(2) 0

lasting 7 days.102

2

generally mild, and one patient at the CPT-11 dose level of 100 mg/rn2experienced thrornbocytopenia of grade 3. Only one patient experienced anemia of grade 3 after two courses of treatment. Diarrhea ofgrade 3 was observed at the 60/80-mg/rn2 dose level of CFF-11/cisplatin and occurred coincidentally with grade 4 granulocytopenia.Four of five patients who developed granulocytopenia of grade 4lasting 7 days experienced diarrhea of grade 3 (two grade 3 andtwo grade 4). Two patients developed liver dysfunction of grade 3.One of two patients who experienced elevation of transaminase ofgrade 3 received cisplatin and vindesine without CPT-11 followingthe current treatment; however, similar evidence of liver dysfunctionwas not observed. No pulmonary toxicity related to drug administration was recorded in these trials. In addition, neurological or renaltoxicity, which is generally attributable to cisplatin and vindesine, didnot increase with increasing doses of CPT-11. The MiD in the secondphase I trial was 100 mg/rn2 CPT-11 on days 1 and 8 combined withlow-dosecisplatin (60 mg/rn2)andvindesine(Table4).

Granulocytopenia and diarrhea were observed in the second phaseI trial (Table 5). The granulocyte count nadir (median, 428/rnm3;range, 26—3477/nirn3)usually occurred at approximately day 14 (between days 8 and 17), and the median duration of granulocytopenia of<1000/mm3 was 7 days (range, 2—16days). Although wide interpatient variation in the degree of granulocytopenia was noted at eachdose level, the severity of granulocytopenia tended to increase as thedose level increased. Diarrhea usually took the form of frequent smallamounts of caddy or watery stools, was observed from day 10 to day16 after the start of treatment, and occurred coincidentally withgranulocytopenia of grade 4. No patients experienced grossly bloodydiarrhea.

With the combination of CVF-11, cisplatin, and vindesine, theMTDs of CPT-11 combined with either high-dose (100 mg/rn2) orlow-dose cisplatin (60 mg/rn2) were 50 and 100 mg/rn2 on days 1 and8, respectively. No further dose escalation was performed during thesetrials.

Response to Treatment. Table 6 shows the therapeutic responsesof patients treated with this regimen in the second phase I trial. Eightpatients were nonassessable for response. These patients were removed from study after one cycle of treatment for the followingreasons: one had granulocytopenia of grade 4 lasting 7 days and onehad diarrhea of grade 4 at the CPT-11/cisplatin dose level of 60/80mg/rn2, two had granulocytopenia of grade 4 lasting 7 days anddiarrhea of grade 3 and one had liver dysfunction of grade 3 at theCPT-11/cisplatin dose level of 80/60 mg/m2, two had granulocytopenia of grade 4 lasting 7 days and diarrhea of grade @3,and one hadliver dysfunction of grade 3 at the CPT-1 1/cisplatin dose level of100/60 mg/rn2. One patient with only diarrhea of grade 3 as thedose-limiting toxicity received the second course of treatment and wassuccessfully treated without further dose-limiting toxicity.

No patient achieved a complete response. Five of 11 patientsentered from the first level to the fourth level achieved partial responses. Among the patients treated with CPT-1 1 (80 mg/rn2) on days1 and 8 and cisplatin (60 mg/rn2) on day 1, four of eight assessablepatients achieved partial responses. Overall, 10 of 30 patients entered(10 of 22 assessable patients) in the second phase I trial achievedpartial responses. The median duration of response was 28 weeks(range, 10—54weeks).

Pharmacokinetics. Pharmacokinetic data were obtained from sixpatients who were entered in the first phase I study and three patientswho were entered in the second trial (Table 7). In the first trial, the Cmax of CVF-1 1 was observed 0 to 5 mm after the end of CPT-1 1infusion, and the range of the CPT-1 1 C max was 0.41—0.70 @g/ml.The C max of SN-38 was observed during 5—30mm after the end ofCP,r-11 infusion, and the range of the SN-38 C max was 11.7—23.5ng/ml in patients treated with CPT-1 1 at doses of 25—37.5mg/rn2. Inthe second trial, C max and AUC of CPT-1 1 increased in relation tothe dose of CPT-11; however, interpatient variability of C max andAUC of SN-38 was very large. Cases 44 and 45 experienced intractable diarrhea.

No.of patientsNo. of coursesGranulocytopema―Granulocyte counts in all courses

Median nadir (Iji@l) 420 612 352 195 435Range(/,.&l) 242—966 98—2352 40-696 50-1300 26—1260Day nadir [median (range)] 14 (14—15) 13 (10—16) 13 (8—15) 14 (12—17) 15 (12—17)Day recovery [median (range)]― 7 (2—15) 5 (3—9) 6 (3—15) 8 (2—14) 7 (3—16)

Diarrheac -@- — 0/0@ — -@-- —@-_____

aValuesarethe numbersof patientswho exhibitedgrade4 granulocytopenialasting 7 dayswith the first and secondcourses/numberof patientswho exhibitedgrade4granulocytopenialasting 7 daysin all courses.

b Duration of granulocytopenia <1000/gILC Values are the numbers of patients who exhibited grade 3 or 4 diarrhea with the first and second courses/number of patients who exhibited grade 3 or 4 diarrhea in all courses.

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Table 7 CPT Ii and SN-38 pharmacokinetic data in thefirst and second p1wse ItrialsDose

(mg/rn2)CPT-11SN-38%AUCPatientC

max AUCC maxAUCSN-38/No.CFT-11 Cisplatin(p@g/ml) (,.tg/h/ml)(ng/mI)(ng/h/ml)CPT-11First

trial1251000.41 1.7017.2133.37.82251000.48 2.1914.7104.44.8325100034 2.4214.196.64.01037.51000.47 1.5711.752.13.31137.51000.61 3.4414.1136.54.01237.51000.70 2.6223.5187.47.2Second

trial4380600.97 5.9315.193.71.64480601.10 7.0952.4292.04.14580601.20 7.3538.8 209.12.8

PHASE I STUDY OF CPT-11, CISPLATIN, AND VINDESINE IN NSCLC

received antibiotics for fever associated with granulocytopenia. However, in 10 of 12 patients delayed diarrhea occurred prior to the use ofantibiotics. In one of two patients who received antibiotics for 5 to 7days prior to the occurrence of severe delayed diarrhea, stool wasexamined for the presence of enterotoxin D-1 produced by Clostridium difficile. C. difficile, however, was not detected. The mechanismof diarrhea induced by CPT-11 is unclear. Sasaki et a!. (36) reportedthat there was a positive correlation between the AUCs of CPT-11 andthe percentage decrease in leukocyte cell count and that episodes ofdiarrhea were more closely correlated with the AUCS of SN-38 than

those of CPT-1 1. More detailed basic and clinical research concerningthe diarrhea induced by CPT-1 1 will be necessary to clarify this point.

In the current phase I studies of the combination of CPT-11,cisplatin, and vindesine, the recommended i.v. doses for a phase IItrial of CPT-1 1 given on days 1 and 8 and combined with eitherhigh-dose cisplatin (100 mg/rn2) or low-dose cisplatin (60 mg/rn2) are37.5 and 80 mg/rn2, respectively. Although the criteria for MTD in thecurrent studies may be considered slightly aggressive relative tostandard definitions of MTD (grade 3 to 4 toxicity in one-third ormore of patients), they are based, in part, on the relatively rapidlyreversible nature of granulocytopenia and on the paucity of granulocytopenic complications at these doses. And granulocytopenia may beminimized using a hematopoietic growth factor such as G-CSF orGM-CSF in cases with granulocytopenia of grade 3. The criteria ofdose-limiting toxicity and MTD used in the current studies were verysimilar to those used in recent phase I trials of new single agents suchas taxotere or taxol (37—39),in which neutropenia was the majordose-limiting toxicity.

Although the dose intensity of cisplatin in the treatment of advanced non-small cell lung cancer has been debated, high-dose cisplatin has been used widely for this disease. The current studydemonstrated important pharmacokinetic results for CPT-11 (37.5mg/rn2, days 1 and 8) combined with high-dose cisplatin (100 mg/rn2).The dose of 37.5 mg/rn2 CPT-1 1 appears to be quite low (one-fifth)compared with that (100 mg/rn2 weekly) in the previous phase I studyof CPT-11 as a single agent (22). The pharmacokinetic data, however,showed that the C max of SN-38, the active metabolite of CPT-1 1,reached half (range, 14—23.5ng/ml) that of SN-38 when CPT-11 wasadministered at 100 mg/rn2 (36). Moreover, as shown in Table 7, theC max of CPT-11 (>0.4 .tg/rnl) reached >10-fold the concentrationrequired to inhibit growth by 50% seen in in vitro studies (31, 32).Therefore, 37.5 mg/rn2 CPT-1 1 weekly combined with high-dosecisplatin appears to have therapeutic value.

Based on the assumption of a dose-effective relationship, however,CPT-11 could be combined with high-dose cisplatin (100 mg/rn2) andvindesine at only 19% (37.5 mg/rn2 on days 1 and 8) of the doseintensity of 100 mg/m2/week that could be achieved by a single agent(22). Therefore, we conducted a second phase I study of this regimento focus primarily on the dose escalation of CPT-1 1. As a result, thedose of CPT-1 1 combined with low-dose cisplatin (60 mg/rn2) andvindesine could be increased at 40% (80 mg/rn2 on days 1 and 8) ofthe dose intensity of the drug when it was given alone. This doseintensity of CPT-1 1 (40%) was very close to that of CPT-11 (45%)reported by Masuda et aL (40) in their phase I trial of the combinationof CPT-11 and a modest dose of cisplatin (80 mg/rn2), although thecriteria for MTD were different in the two studies.

On the other hand, it is unclear which is important, the doseintensity of cisplatin or dose intensity of CPT-1 1, in the combinationof cisplatin and CPT-1 1 in the management of the patients withadvanced NSCLC. In the current phase I studies, which regimen isactive is unclear because of small number of patients; however, at therecommended dose, high-dose CPT-1 1 combined with low-dose cisplatin seerns to be less toxic, especially gastrointestinal toxicity,

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Table 6 Therapeutic response in second phase I trial

No. of patientsDose (mg/rn2) No. of responding―

Total no. cycles/patientCPT-1 1 Cisplatin patients [median (range)] CR PR SD PD NA

20 60 3 3(2—4) 0 1 1 1 040 60 3 4(2—7) 0 2 1 0 060 60 3 2(2—3) 0 1 2 0 060 80 5 2(1—2) 0 1 1 1 280 60 11 2(1—4) 0 4 4 0 3

100 60 5 1(1—4) 0 1 1 0 3

a CR, complete response; PR, partial response; SD, stable disease; PD, progressivedisease; NA, nonasscssable.

DISCUSSION

CPT-1 1 is a promising new active agent against NSCLC. Doselimiting toxicities were leukopenia and diarrhea in a phase II study(23). The current phase I study of CPT-11 in combination withcisplatin and a fixed dose of vindesine was conducted to determine thetoxicity/morbidity of this regimen in the treatment of patients withmetastatic NSCLC who had received no prior therapy.

The toxicities of this regimen were leukopenia and gastrointestinaltoxicity, especially diarrhea. In the current studies, we defined anabsolute granulocyte count of <500/mm3 for 7 days or more asunacceptable toxicity. The duration of granulocytopenia might bereduced by using recombinant human G-CSF or GM-CSF. In thecurrent studies without G-CSF and GM-CSF, however, granulocytopenia did not induce any delays in treatment or treatment-relateddeaths. On the other hand, diarrhea was a very troublesome side effectof this regimen with almost all patients entered in the study experiencing some degree of diarrhea. Diarrhea of grade 3 or 4 occurredcoincidentally with granulocytopenia of grade 4. In addition, intractable diarrhea induced by CPT-1 1 was associated with the dose ofcisplatin, as shown in Tables 2 and 4. Diarrhea induced by CPT-1 1combined with high-dose cisplatin (100 mg/rn2) was severe, and in thefirst study, the dose of CPT-1 1 could not be escalated >50 mg/rn2because of diarrhea. On the other hand, in the second study in whichlow-dose cisplatin (60 mg/m2) was used, less diarrhea was observedeven at a dose of CPT-1 1 of 60 mg/rn2.

If the patients experienced grade 3 or worse diarrhea, diarrhea wasroutinely managed with 2—6mg loperamide HC1 daily in addition toi.v. fluid and electrolyte replacement; if diarrhea was not controlledwith loperamide, then opiates were used. No prophylactic measureswere undertaken prior to CPT-1 1 treatment. However, diarrheamainly induced by CPT-1 1 was resistant to standard doses of antidiarrheic drugs. Delayed diarrhea of grade 3 or 4 occurred coincidentally with granulocytopenia of grade 4. All 12 patients who experienced delayed diarrhea of grade 3 or 4 in the two phase I studies

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PHASE I STUDY OF c@pi-ii, CISPLATIN, AND VINDESINE IN NSCLC

compared to low-dose CPT-1 1 combined with high-dose cisplatin,probably with equal activity as shown in Tables 3 and 6, and theformer regimen is easily administered to the patients with less vigorous hydration-diuresis.

In the current second phase I study, 10 of 30 patients entered (10 of24 assessable patients) with metastatic NSCLC achieved partial responses. Although no patient achieved a complete response, theresponse data for this regimen appear to be encouraging (41). In thecurrent phase I studies, however, it is unclear whether this regimen isany better than CPT-11 alone or cisplatin alone, and there is synergyfor these agents observed in vitro studies (32). We are now proposinga phase II study of this regimen for ambulatory patients with metastatic NSCLC using 80 mg/rn2 CPT-11 (on days 1 and 8) combinedwith 60 mg/rn2 cisplatin (on day 1) and vindesine (3 mg/rn2 on days1 and 8), every 4 weeks, as a multicenter cooperative trial on the basisof the following: (a) Gralla et aL (24) reportedthat the responserateof a combination of low-dose cisplatin (60 mg/rn2) and vindesineagainst advanced NSCLC was 43%; (b) randomized trials comparinghigh-dose cisplatin (120 mg/rn2) and low-dose cisplatin (60 mg/rn2) incombination with vindesine (24) or etoposide (42) in advancedNSCLC failed to demonstrate a significant survival advantage with ahigh-dose regimen; (c) the dose intensity of CPT-11 combined withlow-dose cisplatin (60 mg/rn2) and vindesine may increase to doublethe dose intensity of the drug combined with high-dose cisplatin (100mg/rn2) and vindesine; and (d) gastrointestinal toxicities were less inpatients treated with low-dose cisplatin (60 mg/rn2) and 80 mg/rn2CP'F-ll than in those treated with high-dose cisplatin (100 mg/rn2)and 37.5 mg/rn2 CPT-11.

ACKNOWLEDGMENTS

We thankDr. John S. Lazo, Departmentof Pharmacology,UniversityofPittsburgh, for his valuable advice.

REFERENCES

1. Bakowski,M.T., andCrouch,J. C. Chemotherapyof non-smallcell lungcancer:areappraisal and a look to the future. Cancer Treat. Rev., 10: 159—172,1983.

2. Joss, R. A@,Cavalli, F., Goldhirsch, A., Mermillod, B., and Brunner, K@W. Newagents in non-small cell lung cancer. Cancer Treat. Rev., 11: 205—236,1984.

3. Bonomi, P. Brief overview of combination chemotherapy on non-small cell lungcancer. Semis. Oncol., 13: 89-91, 1986.

4. Klastersky, J. Therapy with cisplatin and etoposide for non-small-cell lung cancer.Semin. Oncol., 13: 104—114,1986.

5. Rapp, E., Pater, J. L, Willan, A, Cormier, Y., Murray, N., Evans, W. IC, Hodson,D. I., Qark, D. A., Feld, R., Arnold, A. M., Ayoub, J. I., Wilson, K. S., Latreille, J.,Wierzbicki, F., and Hill, D. P. Chemotherapy can prolong survival in patients withadvanced non-small-cell lung cancer. J. Chin.Oncol., 6: 633—641,1988.

6. Dillman, R. 0., Seagram, S. L, Propert, K. J., Guerra, J., Eaton, W. I., Perry, M. C.,Carey, R. W., Frei, E. F., III, and Green, M. R. A randomized trial of inductionchemotherapy plus high-dose radiation versus radiation alone in stage III non-smallcell lung cancer. N. Engl. J. Med., 323: 940-945, 1990.

7. Finkelstein, D. M., Ettinger, D. S., and Ruckdeschel, J. C. Long-term survivors inmetastatic non-small cell lung cancer: an Eastern Cooperative Oncology Group study.J. Clin.OncoL,4: 702—709,1986.

8. Miller, T. P., chen, T. T., Coltman, C. A., O'Bryan, R. M., Vance, R. B., Weiss,0. B., Fletcher, W. 5., Stephens, R. L, and Livingston, R. B. Effect of alternatingcombinationchemotherapyon survivalof ambulatorypatientswithmetastaticlargecell and adenocarcinoma of the lung. A Southwest Oncology Group study. J. Clin.OncoL,4: 502-508,1986.

9. Ruckdeschel, J. C., Finkelstein, D. M., Ettinger, E. S., Creech, R. H., Mason, B. A.,Joss, R. A@,and Vogi, S. A randomized trial of the four most active regimens formetastatic non-small-cell lung cancer. J. Clin. Oncol., 4: 14—22,1986.

10. Sorensen, J. B., Hansen, H. H., Dombemowsky, P., Bark, E., Malmberg, R., Aabo, IC,Bodker, B., and Hansen, M. Chemotherapy for adenocarcinoma of the lung (WHOHI): a randomized study of vindesine versus lomustine, cyclophosphamide andmethotrexate versus all four drugs. J. Clin. Oncol., 5: 1169—1177,1987.

11. Wall,M. E.,Wani,M.C.,Cook,C. E.,Palmar,K. H., MacPhail,A. T., andSimm,0. A. Plant antitumor agents. 1. The isolation and structure of camptothecin, a novelalkaloid leukemia and tumor inhibition from Camptotheca acwninata. J. Am. Chem.Soc., 88: 3888—3890, 1966.

12. Gab, R. C., Whang-Peng, J., and Adamson, R. H. Studies on the antitumor activity,

mechanism of action and the cell cycle effects of camptothecin. J. NatI. Cancer Inst.,46: 789—795,1971.

13. Li, L. H., Fraster, T. J., and Olin, E. J. Action of camptothecin on mammalian cellsin culture. Cancer Res., 32: 2643—2650,1972.

14. Gottlieb, J. A., Guarino, A. M., and Call, J. B. Preliminary pharmacologic and clinicalevaluation of camptothecin sodium (NSC.100880). Cancer Chemother. Rep., 54:461—470,1970.

15. Muggia, F. M., Creaven, P. J., Hansen, H. H., Cohen, M. H., and Selawry, 0. S. PhaseI clinicaltrial of weeklyand daily treatmentwith camptothecin(NSC-100880):correlation with preclinical studies. Cancer Chemother. Rep., 56: 515—521,1972.

16. Moertel, C. G., Schutt, A. 3., and Reitermeier, R. J. Phase II study of camptothecin(NSC-100880) in the treatment of advanced gastrointestinal cancer. Cancer Chemother. Rep., 56: 95—101,1972.

17. Schaeppi, V., Fleischman, R., and Cooney, D. A. Toxicity of camptothecin (NSC100880).CancerChemother.Rep.Part3, 5: 25—36,1974.

18. Kunimoto, T., Nina, K., Tanaka, T., Uehara, N., Baba, H., Takeuchi, M., Yokokura,T., Sawada, S., Miyasaka, T., and Mutai, M. Antitumor activity of 7-ethyl-10-(4-(jiperidino)-1-piperidino)carbonyloxyl-camptothecin, a novel water-soluble denvative of camptothecin, against murine tumors. Cancer Res., 47: 5944—5948,1987.

19. Kaneda, N., Nagata, H., Furuta, T., and Yokokura, T. Metabolism and pharmacokinetics of the camptothecin analogue CPT-11 in the mouse. Cancer Res., 50: 1715—1720, 1990.

20. Taguchi, T., Wakui, A., Hasegawa, IC, Niitani, H., Furue, H., Ohta, K., and Hattori,1. PhaseI clinicalstudyof CPT-11,researchgroupof CPT-11(inJapanese).GanToKagakuRyoho1: 115-120,1990.

21. Greaven, P. J., Allen, L M., and Muggia, F. M. Plasma camptothecin (NSC-100880)levels during a 5-day course of treatment: relation to dose and toxicity. CancerChemother. Rep., 56: 573—578,1972.

22. Negoro, S., Fukuoka, M., Masuda, N., Takada, M., Kusunoki, Y., Matsui, IC,Takifuji, N., Kudoh, S., Niitani, H., and Taguchi, 1. Phase I study of weeklyadministration ofCPT-11. J. NatI. Cancer Inst., 83: 1164—1168,1991.

23. Fukuoka, M., Niitani, H., Suzuki, A., Motomiya, M., Hasegawa, IC, Nishiwaki, Y.,Kuriyama, 1., Ariyoshi, Y., Negoro, S., Masuda, N., Nakajima, S., and Taguchi, T.for the CVF-1 1 Lung Cancer Study Group. A phase II study of CPT-1 1, a newderivative of camptothecin, for previously untreated non-small-cell lung cancer.J. Clin. Oncol., 10: 16—20,1992.

24. Gralla, R. J., Casper, E. S., Kelsen, D. P., Braun, D. W., Jr., Dukeman, M. E., Martini,N., Young, C. W., and Golbey, R. B. Cisplatin and vindesine combination chemotherapy for advanced carcinoma of the lung: a randomized trial investigating twodosage schedules. Ann. Intern. Med., 95: 414—420, 1981.

25. Elliott, J. A., Ahmedzai, S., Hole, D., Dorward, A. J., Stevenson, R. D., Kaye, S. B.,Banham, S. W., Stack, B. H. R., and Calman, IC C. Vindesine and cisplatincombination chemotherapy compared with vindesine as a single agent in the management of non-small cell lung cancer: a randomized study. Eur. J. Cancer Clin.Oncol., 20: 1025—1032,1984.

26. Shinkai, T., Saijo, N., Tominaga, IC, Eguchi, IC, Shimizu, E., Sasaki, Y., Fujita. J.,and Futami, H. Comparison of vindesine plus cisplatin or vindesine plus mitomycinin the treatment of advanced non-small cell lung cancer. Cancer Treat. Rep., 69:945—951, 1985.

27. Dhingra, H. M., Valdivieso, M., Can, D. T., Chiuten, D. F., Farha, P., Murphy,W. IC, Spitzer, G., and Umsawasdi, 1. Randomized trial of three combinations ofcisplatin with vindesine and/or VP-16—213in the treatment of advanced non-smallcell lung cancer. J. Chin. Oncol., 3: 176—183,1985.

28. Fukuoka, M., Masuda, N., Furuse, K., Negoro, S., Takada, M., Matsui, K., Takifuji,N., Kudoh, S., Kawahara, M., Ogawara, M., Kodama, N., Kubota, IC, Yamamoto, M.,and Kusunoki, Y. A randomized trial in inoperable non-small cell lung cancer:vindesine and cisplatin versus mitomycin, vindesine, and cisplatin versus etoposideand cisplatin alternating with vindesine and mitomycin. J. Chin.Oncol., 9: 606—613,1991.

29. Shinkai, T., Eguchi, IC, Sasaki, Y., Tamura, T., Ohe, Y., Kojima, A., Oshita, F., andSaljo,N.Arandomizedclinicaltrialofvindesinepluscisplatinversusmitomycinplusvindesine plus cisplatin in advanced non-small cell lung cancer. Eur. J. Cancer, 27:571—575,1991.

30. Lilenbaum, R. C., and Green, M. R. Novel chemotherapeutic agents in the treatmentof non-small-cell lung cancer. J. am. Oncol., 11: 1391—1402,1993.

31. Kanzawa, F., Sugimoto, Y., Minato, IC, Kasahara, IC, Bungo, M., Nakagawa, IC,Fujiwara, Y., Liu, L F., and Saijo, N. Establishment of a camptothecin analogue(CPT.1 1)-resistant cell line of human non-small cell lung cancer: characterization andmechanism of resistance. Cancer Res., 50: 5919—5924,1990.

32. Kano, Y., Suzuki, K., Akutu, M., Suds, K., Inouc, Y., Yoshida, M., Sakamoto, S., andMiura, Y. Effects of CPT-11 in combination with other anti-cancer agents in culture.mt.i. Cancer,50:604—610,1992.

33. Kasahara, IC, Fujiwara, Y., Nishio, IC, Ohmori, T., Sugimoto, Y., Komiya, K.,Matsuda, 1., and Saijo, N. Metallothionein content correlates with the sensitivity ofhuman small cell lung cancer cell lines to cisplatin. Cancer Res., 5!: 3237—3242,1991.

34. Grading toxicity. In: R. E. Wittes (ed), Manual of Oncologic Therapeutics, pp.628—632.Philadelphia: Lippincott, 1989/1990.

35. Gilbaldi, M., and Perrier, D. Pharmacokinetics, Ed. 2. New York: Marcel Dekker,1982.

36. Sasaki, Y., Morita, M., Miya, T., Shinkai, T., Eguchi, IC, Tamura, T., Ohe, Y., andSaijo,N. Pharmacokinetic(PK)andpharmacodynarnic(PD)analysisof CFF-11andits active metabolite SN-38 (Abstract 264). Proc. Am. Soc. Clin. Oncol., ii: I 11,1992.

37. Bums, H., Irvin, R., Kuhn, J., Kalter, S., Smith, L, Shaffer, D., Fields, S., Weiss, G.,Eckardt, J., Rodriguez, G., Rinaldi, D., Wall, J., Cook, G., Smith, S., Vreelan, F.,

2641

on June 23, 2018. © 1994 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from

PHASE I STUDY OF CFr-11, CI5PLATIN, AND VINDESINE IN NSCLC

Bayssas, M., LeBail, N., and Von Hoff, D. Phase I clinical trial of taxotere admin.istered as either a 2-hour or 6-hour intravenous infusion. J. Clin. Oncol., 11: 950—958,1993.

38. Bissett, D., Setanoians, A., Cassidy, J. Graham, M. A., Chadwick, G. A.. Wilson, P.,Auzuannet, V., Le Bail, N., Kaye, S. B., and Kerr, D. J. Phase I and pharmacokineticstudy of taxotere (RP 56976) administered as a 24-hour infusion. Cancer Res., 53:523—527,1993.

39. Wiernik, P. H., Schwartz, E. L., Einzig, A., Strauman, J. J., Lipton, R. B., andDutcher, J. P. Phase I trial of taxol as a 24-hour infusion every 21 days: responsesobserved in metastatic melanoma. J. Clin. Oncol., 5: 1232—1239,1987.

40. Masuda, N., Fukuoka, M., Takada, M., Kusunoki, Y., Negoro, S., Matsui, IC, Kudoh,

S., Takifuji, N., Nakagawa, K., and Kishimoto, S. CPT-11 in combination withcisplatin for advanced non-small-cell lung cancer. J. Clin. Oncol., JO: 1775—1780,1992.

41. Simon, R. Optimal two-stage designs for phase II clinical trials. Controlled Clin.Trials, 10: 1—10,1989.

42. Klastersky, J., Sculier, J. P., Ravez, P., Libert, P., Michel, J., Vandermoten, G.,Rocmans,P., Bonduelle,Y., Mairesse,M.,Michiels,1., Thiriaux,J., Mommen,P.,Dalesio, 0., and the EORTC Lung Cancer Working Party. A randomized studycomparing a high and a standard dose of cisplatin in combination with etoposide inthe treatment of advanced non-small-cell lung cancer. J. Chin. Oncol., 4: 1780—1786,1986.

2642

on June 23, 2018. © 1994 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from

1994;54:2636-2642. Cancer Res   Tetsu Shinkai, Hitoshi Arioka, Hiroshi Kunikane, et al.   in Advanced Non-Small Cell Lung Cancercin, and Cisplatin in Combination with Fixed Dose of Vindesine7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothePhase I Clinical Trial of Irinotecan (CPT-11),

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