Background Oxaliplatin (L-OHP) is a platinum complex that possesses activity against human and murine cells in vitro and in vivo, including colorectal carcinoma-derived cell lines, and cells that have been selected for resistance to cisplatin. We report two consecutive phase H trials of L-OHP for treatment of patients with advanced colorectal carcinoma. Patients and methods: Fifty-eight patients were entered in study I, and 51 patients in study II. All of the patients had tumor progression when they were treated, prior to their enrolment, with a fluoropyrimidine-containing regimen. In both trials treatment consisted of L-OHP, 130 mg/m2 by i.v. infusion for two hours; the treatment was repeated every 21 days. Results Response to therapy: Study I: Fifty-five patients were assessed for response. The response rate was 11% (95% CI, 0.03-0.19). Study II: All 51 patients were assessed for response. The response rate was 10% (95% CI, 0.017-0.18). The overall response rate for the 106 evaluated patients was 10% (95% CI, 0.046-0.16). Times to disease progression in responders were 4, 4, 4.5+, 5, 5, 6, 6, 6, 6+, 9, and 13 months. The dose-limiting toxic effect was sensory peripheral neuropathy. The incidence of severe peripheral neuropathy grades was: Study I: grade 3, 23% of patients, and grade 4, 8% of patients. Study II: grade 3, 14% of patients, and grade 4, 4% of patients. Severe neuropathy had a favorable course in all of the patients who had long-term neurologic follow-up. Diarrhea and myeloid impairment were minor. Conclusion L-OHP produced modest, but definite antitumor activity in patients with advanced colorectal carcinoma who were previously resistant to chemotherapy including fluoropyrirnidines. Toxicity is within acceptable limits of tolerance at the dose and schedule of oxaliplatin used in this tria

Abad, A.

Brienza, S.

de Gramont, A.

Diaz-Rubio, E.

François, E.

Gamelin, E.

Gastiaburu, J.-J

Itzhaki, M.

Machover, D.

Marty, M.

Metzger, G.

N'Daw, D.

Sastre, J.

Schif, A.

Seitz, J.-F

Vignoud, J.

Ychou, M.

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Annals of Oncology 7: 95-98, 1996.© 1996 Kluwer Academic Publishers. Primed in the Netherlands.Short reportTwo consecutive phase II studies of oxaliplatin ( L - O H P ) for treatment ofpatients with advanced colorectal carcinoma who were resistant to previoustreatment with fluoropyrimidinesD. Machover,111 E. Diaz-Rubio,212 A. de Gramont,3 A. Schilf,1 J.-J. Gastiaburu,14S. Brienza,1'4 M. Itzhaki,1 G. Metzger,1 D. N'Daw,1 J. Vignoud,4 A. Abad,5 E. Francois,6E. Gamelin,7 M. Marty,8 J. Sastre,2 J.-E Seitz9 & M. Ychou101 Department of Hematology and Oncology, Hospital Paul Brousse, VMejuif, France; 2Service of Oncology, Hospital San Carlos, Madrid,Spain; iService of Internal Medicine, Hospital Saint-Antoine, Paris, France; 'Debiopharm Laboratories, Lausanne, Switzerland; 5 Hospitalof Badalona, Barcelona, Spain; 6 Centre Antoine Lacassagne, Nice; n Centre Paul Papin, Angers, France; i Service of Oncology, HospitalSaint-Louis, Paris; 9 Institute Paoli-Calmettes, Marseilles; wCentre Paul Lamarque, Montpellier, France; "Coordinator of study I;^Coordinator of study II* See page 98 for list of other investigators and centersSummaryBackground: Oxaliplatin (L-OHP) is a platinum complex thatpossesses activity against human and murine cells in vitroand in vivo, including colorectal carcinoma-derived cell lines,and cells that have been selected for resistance to cisplatin.We report two consecutive phase II trials of L-OHP for treat-ment of patients with advanced colorectal carcinoma.Patients and methods: Fifty-eight patients were entered instudy I, and 51 patients in study II. All of the patients hadtumor progression when they were treated, prior to theirenrolment, with a fluoropyrimidine-containing regimen. Inboth trials treatment consisted of L-OHP, 130 mg/m2, by i.v.infusion for two hours; the treatment was repeated every 21days.Results: Response to therapy: Study I: Fifty-five patientswere assessed for response. The response rate was 11% (95%CI, 0.03-0.19). Study II: All 51 patients were assessed forresponse. The response rate was 10% (95% CI, 0.017-0.18).The overall response rate for the 106 evaluated patients was10% (95% CI, 0.046-0.16). Times to disease progression inresponders were 4, 4, 4.5+, 5, 5, 6, 6, 6, 6+, 9, and 13months. The dose-limiting toxic effect was sensory peripheralneuropathy. The incidence of severe peripheral neuropathygrades was: Study I: grade 3, 23% of patients, and grade 4,8% of patients. Study II: grade 3,14% of patients, and grade4, 4% of patients. Severe neuropathy had a favorable coursein all of the patients who had long-term neurologic follow-up.Diarrhea and myeloid impairment were minor.Conclusion: L-OHP produced modest, but definite anti-tumor activity in patients with advanced colorectal carci-noma who were previously resistant to chemotherapy includ-ing fluoropyrimidines. Toxicity is within acceptable limits oftolerance at the dose and schedule of oxaliplatin used in thistrial.Key words: advanced colorectal carcinoma, oxaliplatin,phase II studyIntroductionOxaliplatin [trans-L-l,2-diaminocyclohexane] oxalato-platinum (II), (L-OHP) is a platinum complex with anoxalato ligand as leaving group and a 1,2-diamino-cyclohexane (dach) carrier [1, 2]. The drug exerts anti-tumor activity against a number of human and murinetumor cells in vitro and in vivo, including colorectalcancer-derived cell lines [1-4]. It possesses a highercytotoxic potency on a molar basis than do cisplatinand paraplatin [3], and it is active on various cell linesthat have been selected for resistance to cisplatin [3,4],Preliminary studies have suggested that combinationtherapy with 5-fluorouradl (5-FU) and L-OHP is syn-ergjstic against L1210 leukemia transplanted into micePI-Toxic effects of oxaliplatin include peripheral neuro-pathy, vomiting, diarrhea, and mild myelosuppression.The drug has no renal toxicity [2, 5]. L-OHP given ata circadian rhythm-modulated i.v. infusion rate topatients with advanced colorectal carcinoma yieldedresponse rates of 58% when given in combination with5-FU and folinic acid irrespective of the patients' pre-vious treatment status [6].Patients and methodsPatients (Table 1)Each patient was required to have a previously diagnosed colorectalcarcinoma with metastases that could be measured by CT scan. Forinclusion, patients had to have confirmed tumor progression whenthey had been treated with a fluoropyrimidine-containing regimen.Patients with any of the following conditions were not eligible for96Table 1. Patient characteristics.Characteristic No. of patients (%)Study I Study HNo. of patients entered 58 51Age range, years39-50 6 (10) 9 (18)51-60 19 (33) 15 (29)61-75 33 (57) 27 (53)SexMale 36 (62) 32 (63)Female 22 (38) 19 (37)Site of primary tumorColon 38 (66) 28 (55)Rectum 20 (34) 23 (45)ECOG performance status0-1 50 (86) 46 (90)2 7 (12) 5 (10)3 1 (2)Sites of metastatic tumor involvementLiver only 30 (52) 20 (39)Liver and other sites1 18(31) 20(39)Other sites" 10(17) 11(22)Number of sites of tumor involvement1 40 (69) 31 (61)2 17 (29) 17 (33)3 1 (2) 3 (6)Previous dose of 5-FU in g/m2 c<30 21(36) 34(67)31-60 19(33) 15(29)>60 18 (31) 2 (4)No. of prior regimens of chemotherapy111 24 (41) 39 (76)2 33 (57) 9 (18)3 1 (2) 3 (6)* Including lung, adrenals, lymph nodes, bone, ovaries, perito-neum, pelvis, and spleen.b Including lymph nodes, pelvis, and peritoneum.c Median doses of 5-FU given to patients prior to their enrolmentin study I and study II were 40 g/m2 (range, 6-134 g/m2) and 23g/m2 (range, 5-76 g/m2), respectively.d Previous fluoropyrimidine-containing regimens comprised 5-FUand folinic acid (FA), and 5-FU with FA combined with hydroxy-urea, a-interferon, mitomycin C, lomustine, methotrexate, pyra-rubicine, or etoposide, and ftorafur as a single agent.the studies: CNS metastases, bone metastases, or serosal effusions asthe sole indicator of tumor; any prior cisplatin- or paraplatin-con-taining chemotherapy, performance status (ECOG) >2, a serumalkaline phosphatase or bilirubin level above twice the upper limit ofthe normal range, or creatinine clearance <60 ml/min. Writteninformed consent was obtained, and administrative requirementswere met.Two phase II studies were performed consecutively. Fifty-eightpatients were included in study I. Of these, three had tumors thatcould not be measured. After completion of study I, we started asecond trial (study n), which accrued 51 patients, all of them evalu-able for response to therapy. The 109 patients enrolled in studies Iand II were evaluated for toxic effects. Studies I and II were con-ducted by different groups of investigators.Treatment protocolTherapy consisted of a single i.v. infusion of L-OHP at a dose of 130mg/m2, repeated every 21 days. The dose of the drug was chosen onthe basis of recommendations of the published phase I studies [2, 5].L-OHP (Debiopharm SA., Lausanne, Switzerland) was provided asa lyophilised powder. It was reconstituted in a solution of 5% dex-trose in water at a final concentration of L-OHP of 2 mg/ml. Thesolution was infused i.v. over 2 hours. Patients received no pre-hydration. The dose of L-OHP was reduced by 25% in instances ofWHO grade 3 granulocytopenia or thrombocytopenia, or of grade 3peripheral neuropathy according to the scale in Table 2. A singlegrade 4 episode of any of these toxic effects led to discontinuation ofthe treatment. All patients were given antiemetics.Patient evaluationBefore each treatment course, patients underwent a clinical exam-ination and blood cell counts, liver function tests and determina-tions of serum creatinine. Patients were monitored for antitumorresponse after sets of 3 consecutive courses. Plasma CEA and CA19-9 levels were measured in all patients. Response was determinedquantitatively by comparison of the size of all measurable lesions,as evidenced on CT scan. Objective responses were categorizedaccording to the WHO criteria. Response to therapy was deter-mined initially by the radiologist and the patient's clinician, and by asecond-party review for final evaluation. The times to disease pro-gression were calculated from the date of initiation of therapy. Sur-vival analysis and plotting of cumulative probability of the incidenceof neuropathy according to dose were performed by the method ofKaplan and Meier.ResultsToxic effectsStudy I. The 58 patients received a total of 314 coursesof L-OHP (range, 1-16 courses per patient; median, 5courses) which were evaluated for toxicity (Table 2).The median cumulative dose of L -OHP given to pa-tients during study I was 650 mg/m2 (range, 130-1990mg/m2).Table 2. Toxic effects.Toxic effectDiarrhea'Nausea/vomiting'Granulocytopenia*Anemia*Thrombocytopenia*Peripheral neuro-pathy1"Increase in serumcreatinine*StudyIUIniiiiiiiIIiniIIPercent of patients withGrade0557026408994657477882495100Grade1211134225627199828375 d-Grade2141923304-651443941--tenacity0Grade310-1762-22--2314--Grade4_--2------84--* Graded according to WHO.b Grade 1: dysesthesia and/or paresthesia, transient, <7 days; grade 2: dys-esthesia and/or paresthesia, transient, < 14 days; grade 3: dysesthesia and/orparesthesia persisting during the drug-free interval between courses; grade 4:severe dysesthesia and/or hypoesthesia with functional impairment.c Fifty-eight patients were assessed for tenacity in study I, and 51 patients instudy II. For patients who had >2 episodes of the same toxic effect, only thehighest grade of toxicity is reported in the table.d Single episodes of transient increase to < l j x the upper limit of the normalrange.97Diarrhea was a toxic effect in 45% of the patients;10% of them had grade 3 diarrhea, and grade 3 vom-iting was observed in 17%. Myelosuppression was mild.Transient increase in the serum creatinine level to<1.5x the upper limit of the normal range was ob-served in 5% of the patients.Sensory peripheral neuropathy was observed in98% of the patients. Grades were 1 in 28%, 2 in 39%, 3in 23%, and 4 in 8% of the patients. The incidence andseverity of the peripheral neuropathy rose with increas-ing cumulative doses of L-OHP. A correlation wasfound between the increasing grades of the neuropathyand the total amounts of the drug given to patients(Spearman Correlation Test, p < 0.00001). At cumula-tive doses of <780 mg/m2 of L-OHP, grades 3 and 4peripheral neuropathy were observed in 14% and 4%of patients, respectively. The projected probability forpatients to have neuropathy of grades 3 or 4 after theyreceived cumulative L -OHP doses of 780 mg/m2 was22%. A number of patients had long-term neurologicfollow-up after discontinuation of L-OHP. Of the 13patients who had grade 3 neuropathy, 5 had disappear-ance of all symptoms at between 2 and 4 months, 2patients had major attenuation after 2-5 months, and 6patients had no long-term follow-up. Of the 5 patientswho had grade 4 neuropathy, 1 had disappearance ofsymptoms after 2 months, 2 had partial regression at 3and 5 months, and 2 had no long-term follow-up. Dur-ing the infusion time of L-OHP, one patient had a tran-sient episode of dyspnea sine materia of unknowncause.Study II. The 51 patients received 203 courses of L-OHP (range, 2-8 courses per patient, median, 3courses) which were evaluated for toxicity (Table 2).The median cumulative dose of oxaliplatin given to pa-tients during study II was 390 mg/m2 (range, 260-1010mg/m2).Thirty percent of patients had grades 1 or 2 diar-rhea. Grades 3 or 4 vomiting was observed in 8% ofpatients. Myeloid toxicity was mild.Sensory peripheral neuropathy was noted in 96% ofthe patients. Grades were 1 in 37%, 2 in 41%, 3 in14%, and 4 in 4% of patients. As in study I, the inci-dence and severity of the peripheral neuropathy rosewith increasing cumulative doses of L-OHP. A correla-tion was found between increasing grades of the neuro-pathy and the total dose of the drug administered topatients (Spearman Correlation Test, p - 0.0001). Ofthe 9 patients who had grades 3 and 4 neuropathy, 2had disappearance of all symptoms and 7 had attenua-tion of symptoms at between 3 and 6 months after dis-continuation of L-OHP. However, follow-up was tooshort for precise evaluation of the regression potentialof the neuropathy.Response to therapyStudy I. The median follow-up time for the 55 evalu-able patients was 7 months (range, 1-18.5 months). Sixpatients attained a PR The response rate was 11%(95% Q , 0.03-0.19). Times to disease progression inresponders were 5, 5, 6, 6, 6+, and 13 months. Thetime required for achievement of response was 6 weeksin all patients. The median survival time of the 58patients was 8.2 months. Survival times of the respond-ers were 9, 9+, 12,14.5,15, and 18.5 months. Twenty-three patients (42%) had NC, and 26 patients (47%)had PD.Study II. The median follow-up time for the 51 pa-tients was 4.5 months (range, 1-13 months). Fivepatients attained a PR The response rate was 10%(95% CI, 0.017-0.18). Times to disease progression inresponders were 4, 4, 4.5+, 6, and 9 months. The timerequired for achievement of response was 6 weeks in 4patients and 12 weeks in 1 patient. Survival times ofresponders were 4+, 5.5, 6+, 7+, and 12 months. Six-teen patients (31%) had NC, and 30 patients (59%)had PD.The overall response rate for the 106 evaluablepatients treated in the 2 trials was 10% (95% CI, 0.046-0.16). For patients who attained a PR, ratios of initialCEA titer/final CEA liter (in ng/ml) were 2558/19,77/7,161/38,610/153,453/291, and 25/11 in study I,and 185/7, 230/22, 35/8, 3000/1000, and 23/8 instudy II; ratios of initial CA 19-9 titer/final CA 19-9titer (in units/ml) were 628/32, 2700/380, 106/50,76/42, 21/15, and 370/380 in study I, and 294/24,220/24,900/388,270/140, and 67/39 in study H.DiscussionCisplatin (CDDP) and paraplatin (CBDCA) have failedin the past to demonstrate significant antitumor activityin patients with colorectal carcinoma. When they wereadministered as single agents, these drugs yielded re-sponse rates of 0% to 9% for CDDP [7, 8] and 0%to 5% for CBDCA [9]. In these studies, the meanresponse rates achieved by patients who had previouslyreceived chemotherapy were 3% and 2% for CDDPand CBDCA, respectively. Moreover, combinationtreatment with 5-FU and cisplatin did not produce agreater response rate than that observed with 5-FUgiven as a single agent [10].In the present phase II trials with oxaliplatin, re-sponse rates were 11% and 10% in study I and study n,respectively. These apparently modest results comparefavorably with those obtained with CDDP andCBDCA [7-9], and they may indicate a significanttherapeutic activity of L-OHP because they were ob-tained in patients with tumors who had demonstratedPD during prior therapy including the use of fluoro-pyrimidines (Table 1).The dose-limiting toxic effect of oxaliplatin was sen-sory peripheral neuropathy, which occurred in almostall of the patients. The major symptom was dysesthesia,98which predominated in the limbs and the mucosae ofthe upper aerodigestive tract; it was often triggered byexposure to cold temperatures. The incidence andseverity of the peripheral neuropathy rose with increas-ing cumulative amounts of L-OHP. The projected prob-ability for patients to have neuropathy of grades 3 or 4after receiving a cumulative dose of 780 mg/m2 (i.e.,the amount of drug given in 6 courses of therapy) was22%. Despite its high incidence, the severe neuropathyhad a favorable course after discontinuation of oxali-platin in patients who underwent a long-term neuro-logic assessment during their follow-up. Therefore,neuropathy should be considered to be within accept-able limits of tolerance at the dose and schedule ofL - O H P used in the present study. However, we recom-mend cessation of treatment if neuropathy of grades> 3 appears.Oxaliplatin has major similarities with tetraplatin[tetracMoro(D,L-trans)l,2-diaminocyclohexane platinum(TV)], a platinum complex which, like L-OHP, has a(dach) carrier ligand [3]. However, early clinical studiesof tetraplatin have shown that this drug, unlike oxali-platin, produced severe toxic effects which have pre-vented its further development. The better toxicityprofile of oxaliplatin over that reported for tetraplatinfurther supports the future development of L -OHP forclinical use.Preclinical data on L -OHP included a possiblepotentiation of 5-FU [2]. Therapy with 5-FU, folinicacid, and oxaliplatin given at a circadian rhythm-modu-lated infusion rate produced high response rates inpatients with advanced colorectal carcinoma, whichsuggests that potentiation may occur in this tumor asweU [6].In the present studies, we have demonstrated thatoxaliplatin possesses modest, but definite activity inpatients with advanced colorectal carcinoma who werepreviously resistant to chemotherapy which includedfluoropyrimidines. The data reported here will serve asa basis for future studies of L -OHP in various doses andschedules, in combination with 5-FU and folinic acid,for determination of the therapeutic potential of thedrug.AcknowledgmentsThis present work was sponsored, in part, by Debio-pharm SA., 17, rue des Terreaux, Lausanne, Switzer-land.We acknowledge Melisende Bart and Didier Bertfor secretarial work, and Elisabeth Lanzl for editorialassistance.* Other investigators and centers participating in thetrialsAndres Cervantes, University Hospital, Valencia, Spain; ThierryConroy, Centre Alexis Vautrin, Nancy, France; Hernan Cortes-Funes, Hospital 12 de Octubre, Madrid, Spain; Maxime Malet, Hos-pital of Pau, France; Zrinka Mrsic, Institute for Tumors and AlliedDiseases, Zagreb, Croatia; Joao Oliveira, Institute of Oncology, Lis-bon, Portugal; and Jean-Louis Wendling, Hospital Saint-Louis,Toulon, France.References1. Tashiro T, Kawada Y, Sakurai Y, Kidani Y. Antitumor activityof a new platinum complex, oxalato (trans-l-l,2-diaminocyclo-hexane) platinum (II): New experimental data. Biomed Phar-macother 1989; 43: 251-60.2. Mathe G, Kidani Y, Segiguchi M et al. Oxalatoplatinum orL-OHP, a third-generation platinum complex: An experimentaland clinical appraisal and preliminary comparison with cis-platinum and carboplatinum. Biomed Pharmacother 1989; 43:237-50.3. Pendyala L, Creaven PJ. In vitro cytotoxicity, protein binding,red blood cell partitioning, and biotransfonnation of oxali-platin. Cancer Res 1993; 53: 5970-6.4. Dorr RT, Von Hoff DD. Oxaliplatin. In Appleton and Lange(eds): Cancer Chemotherapy Handbook. Norwalk, CT 1993;758-61.5. Extra JM, Espie M, Calvo F et al. Phase I study of oxaliplatin inpatients with advanced cancer. Cancer Chemother Pharmacol1990; 25: 299-303.6. Levi F, Misset J-L, Brienza S et al. A chronopharmacologicphase D clinical trial with 5-fluorouracil, folinic acid, and oxali-platin using an ambulatory multichannel programmable pump.Cancer 1992; 69: 893-900.7. Desimone PA, Davila E, Jochimsen PR, Bartolucci AA. Highdose cisplatin in the treatment of advanced adenocarcinoma ofthe colon and rectum: A Southeastern Cancer Study Grouptrial. Cancer Treat Rep 1986; 70: 1229-30.8. Lokich J, Zipoli T, Greene R et al. Protracted low-dose cis-platin infusion in advanced colorectal cancer. Cancer TreatRep 1986; 70: 523-34.9. Nole F, Biganzoli L, Buzzoni R, Bajetta E. Carboplatin inpatients with advanced colorectal cancer pretreated withfluoropyrimidines. Eur J Cancer 1993; 29:1330-1.10. Diaz-Rubio E, Jimeno J, Anton A et al. A prospective ran-domized trial of continuous infusion 5-fluorouracil (5-FU) ver-sus 5-FU plus cisplatin in patients with advanced colorectalcancer. A trial of the Spanish Cooperative Group for DigestiveTract Tumor Therapy (T.T.D.). Am J Clin Oncol 1992; 15:56-60.Received 14 August 1995; accepted 7 November 1995.Correspondence to:David Machover, M.D.Departement des Maladies Sanguines et TumoralesHopital Paul Brousse14, avenue Paul-Vaillant Couturier94804, VillejuifFrance

Two consecutive phase II studies of oxaliplatin (L-OHP) for treatment of patients with advanced colorectal carcinoma who were resistant to previous treatment with fluoropyrimidines

Two consecutive phase II studies of oxaliplatin (L-OHP) for treatment of patients with advanced colorectal carcinoma who were resistant to previous treatment with fluoropyrimidines

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