Cerny, T.

Dunlop, D.

Epelbaum, R.

Hanauske, A.

Judson, I.

Kaplan, S.

Roelvink, M.

Schaefer, B.

Smyth, J.

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Annals of Oncology 8:604-606, 1997.© 1997 Kluwer Academic Publishers. Printed in the Netherlands.Short reportPhase II trial of the oral platinum complex JM216 in non-small-cell lungcancer: An EORTC early clinical studies group investigationI. Judson,1 T. Cerny,2 R. Epelbaum,3 D. Dunlop,4 J. Smyth,5 B. Schaefer,6 M. Roelvink,6S. Kaplan7 & A. Hanauske8'Royal Marsden NHS Trust, London, UK; 2lnselspital, Berne, Switzerland; iRambam Medical Center, Haifa, Israel; iBeatson Oncology Centre,Glasgow, i Western General Hospital, Edinburgh, UK; 6New Drug Development Office, Amsterdam, the Netherlands; "''Kantonspital, Basel,Switzerland; s Technical University, Munich, GermanySummaryBackground: JM216 is a new oral platinum complex with dose-limiting toxicity myelosuppresssion, now undergoing phase IIevaluation.Patients and methods: JM216 was evaluated as first linetherapy in non-small-cell lung cancer. Seventeen patients re-ceived 120 mg/nr/day for five days repeated every three weeks.Results: Toxicity was manageable, the commonest side-effects being nausea, vomiting, diarrhoea, constipation andasthenia. Myelososuppression was generally grade < 2 andthere were no cases of neutropenic sepsis or bleeding. Thirteenpatients were fully evaluable for response. No sustained objec-tive responses were reported. One patient was reported asstable disease had a partial response after three courses butwas progressing again after four. An additional five patientshad stable disease (46.2%).Conclusions: Although some patients may have had usefulpalliation, JM216 did not appear to have significant antitu-mour activity in non-small-cell lung cancer.Key words: JM216, lung cancer, non-small cell, oral chemo-therapy, platinumIntroductionLung cancer is one of the leading causes of death in menand women [1]. Non-small-cell lung cancer usuallypresents as a systemic disease for which palliative treat-ment only is available. Single agent chemotherapy hasbeen studied extensively in this disease, with cisplatinproducing the most consistent response rates in theregion of 20% [2]. An oral platinum agent with mildtoxicity would be of value in this setting.The ammine/amine platinum (IV) dicarboxylates [3]were developed with the intention that their enhancedlipophilicity and stability would both improve drug ab-sorption and reduce local toxicity within the gut com-pared with cisplatin and carboplatin. Bis(acetatato) am-mine cyclohexylamine dichloro platinum (IV), or JM216,was chosen for clinical development due to superior oralactivity in vivo compared with cisplatin, carboplatin andtetraplatin [4], and a favourable toxicity profile withdose-limiting myelosuppression [5, 6].In a phase I study of JM216 using a single oral dosedaily x 5 every three to four weeks, the maximumtolerated dose was 140 mg/m2/day. The dose-limitingtoxicity was myelosuppression, non-haematological tox-icities were mild and some evidence of antitumour activ-ity was observed [7]. Starting doses of 100 mg/m2/day x 5 for previously treated patients and 120 mg/m2/day x 5 for previously untreated patients were recom-mended for phase II evaluation using this schedule. Thisphase II study was conducted in previously untreatedpatients with locally advanced, unresectable or meta-static non-small-cell lung cancer.Patients and methodsEligibilityInclusion criteria were histologically or cytologically verified non-small-cell lung cancer >1 , bidimensionally measurable lesion, WHOperformance status (PS) ^ 2 , age >18 years, adequate bone marrowfunction, creatinine < 140 (imol/1 and if > 100 nmol/1 a creatinineclearance >60 ml/min, bilirubin <26 |imol/l and transaminases<2x upper limit of normal unless due to known liver metastases.Exclusions were prior chemotherapy, radiotherapy < 4 weeks previ-ously or to the indicator lesion, and brain or meningeal disease. Allpatients were required to give informed consent according to localethical committee guidelines.Pharmaceutical and treatment informationJM216 was provided by Bristol-Myers Squibb as 10 mg, 50 mg and200 mg capsules and given at a starting dose of 120 mg/m2/day x 5every three weeks or upon bone marrow recovery, i.e. WBC> 3.5 x 109/l, neutrophils > 1.5 x 1O9/1, platelets > 100 x io'/l. Treat-ment could be delayed in the case of renal to.xicity grade > 1, neuro-toxicity grade > 1 and any other unresolved toxicity apart from alopeciaDose modifications were: dose reduction to 100 mg/nr/day for grade 4neutropenia or thrombocytopenia, grade 2 neurotoxicity, or other605grade 3 non-haematological toxicity apart from gastrointestinal oralopecia, withdrawal for grade > 2 nephrotoxicity, grade > 3 neuro-toxicity, grade 4 other toxicity; dose increase to 140 mg/m2/day x5 mthe absence of grade 2 haematological toxicity at nadir or othersignificant toxicities. Patients were considered evaluable for responseafter two cycles, progression after one cycle designating early progres-sion. Concurrent radiotherapy for pain outside the indicator lesion(s)was permitted. The choice of antiemetic treatment was not specifiedand a variety of different regimens were used.Toxicity and response evaluationToxicities were graded according to NCI Common Toxicity Critenaand serious adverse events were reported immediately to the StudyCoordinator. Tumour evaluation was performed prior to and after everytwo cycles of treatment. Physical examination and assessment of perfor-mance status were performed every three weeks, plasma biochemistryevery three weeks and full blood count weekly. Responses were eval-uated according to standard WHO criteria.ResultsPatients and treatmentEighteen patients were registered, 13 male, 5 female,with a mean age of 61 years (range 45-79), 12 patientswere PS 1 and 6 PS 2. Five patients had prior surgery,three prior radiotherapy, and none prior systemic treat-ment. Nine patients had metastatic disease other thanhilar lymphadenopathy at the time of treatment, an addi-tional three patients had disease in mediastinal nodes.One patient received no treatment, three received in-complete treatment during the cycle two and one re-ceived 1/5 the appropriate dose in error. A total of 38courses were administered, four patients received ^ 1dose reductions, in two due to myelosuppression, in onedue to grade 3 diarrhoea, and in one due to a prescribingerror. In four patients the dose was increased to 140 mg/m2/day. Treatment delay occurred in 11 patients withdelays from 1-14 days (median seven days) in six pa-tients due to myelosuppression, in five unrelated to treat-ment. Twelve patients had ^ 2 courses, two patientsreceived five courses.ToxicityPrincipal non-haematological toxicities were nausea andvomiting, diarrhoea, constipation and asthenia. Gastro-intestinal toxicity is given in Table 1. Only 10 patientsTable 1. Incidence of gastrointestinal toxicity in 17 patients receivingJM216 as defined by worst CTC grade per patient.Maximum CTC grade per patientNauseaVomitingDiarrhoeaConstipation0551291541525632321114_1--(55%) received a 5HT3 antagonist with their first courseof JM216, two additional patients received one subse-quently. The remaining patients received dopamine an-tagonists and steroids only. Three patients reportedgrade 3 asthenia which was possibly drug related. Onepatient had grade 3 focal motor neurological toxicity,probably related to occult disease progression. All othernon-haematological toxicities were grade ^ 2.Haematological toxicity was easily manageable. Anae-mia was usually grade ^ 1 and never > 2. Most courses(28 of 38) were associated with grade ^ 1 thrombocyto-penia but there were three cases of grade 3 thrombocy-topenia and three of grade 4. The median platelet nadirfell from 123 x 109/l after course 1 to 54 x 109/l aftercourse 5, but few patients received > 2 courses makingit difficult to draw conclusions from this observation.The majority of patients had no significant leukopeniawhich was grade < 1 in 32 of 38 courses. Only one patienthad grade 3 leukopenia and two grade 3 neutropenia.There were no cases of serious drug-related sepsis.Most serious adverse events were due to disease pro-gression. Treatment was stopped due to toxicity in threepatients, in each case because of myelosuppression, intwo cases prolonged leukopenia and thrombocytopenia,in one case grade 4 thrombocytopenia.ResponseOnly 13 patients were fully evaluable for response. Rea-sons for exclusion were early death in one patient, treat-ment discontinuation in one following myocardial in-farction after two cycles, follow-up evaluation either notdone or performed at the wrong time in two and failureto receive treatment in one. There were no sustainedobjective responses to JM216. One patient had a partialresponse in the primary tumour after three cycles, asmeasured by CT scan, but was progressing again afterfour cycles. The tumour remained smaller than at thestart of treatment and the patient was recorded as stabledisease. An additional five patients were reported as nochange. Four patients continued treatment after twocycles due to stable disease or symptomatic benefit.There were seven cases of progressive disease, four ofthem early.DiscussionThe oral platinum complex JM216 was well tolerated inthis group of patients with non-small-cell lung cancer.Subjective toxicities were generally ^ grade 2 althoughnausea, vomiting, diarrhoea and asthenia could be moresevere. Haematological toxicity was surprisingly lowwith almost no grade >2 leukopenia or neutropenia.Neutropenic sepsis was not observed. Thrombocytope-nia was more frequent but was grade ^ 2 following 84%of courses administered. There were no problems withbleeding related to thrombocytopenia. Four patients(23% of patients treated) had their dose increased from606120 to 140 mg/m2/day. Treatment delay occurred in sixpatients due to delayed haematological recovery andtherefore it may be more appropriate for treatment tobe repeated every four weeks rather than every three asintended in this study.The lack of objective antitumour activity was disap-pointing with no sustained objective responses with 13patients evaluable for response. Nevertheless, of thesepatients six had stable disease (46.2%) and there wassome evidence of disease palliation. In studies withsingle agent cisplatin, response rates were in the orderof 20% [2] and there was also said to be a dose-responserelationship. Carboplatin may be somewhat less active,with an overall response rate in the region of 12% [8]. Itmust be acknowledged that JM216 as a single agentgiven according to this dose and schedule is inactive innon-small-cell lung cancer but randomised studies wouldbe required to define properly its role in combinationwith agents of proven activity.reactions of a new class of orally active Pt(IV) antitumour com-plexes. In Howell SB (ed): Platinum and Other Metal CoordinationCompounds in Cancer Chemotherapy. New York. Plenum Press1991; 93-100.4. Kelland LR, Abel G, McKeage MX Preclinical antitumour evalua-tion of bis-acetato-ammine-dichloro-cyclohexylamine platinum(IV): An orally active platinum drug. Cancer Res 1993; 53. 2581-6.5. McKeage MJ, Morgan SE, Boxall FE et al. Preclinical toxicologyand tissue distribution of novel oral antitumour platinum com-plexes: Ammine/amine platinum (IV) dicarboxylates. Cancer Che-mother Pharmacol 1994; 33. 497-503.6. McKeage MJ, Morgan SE, Boxall FE et al. Lack of nephrotoxicityof oral ammine/amine platinum (IV) dicarboxylate complexes inrodents. Br J Cancer 1993; 67: 996-1000.7. Judson I, McKeage M, Raynaud Fet al. A phase I trial of the oralplatinum anticancer drug JM216 complex [Af-6/j(acetato)-B-ammine-cd-dichloro-E-cyclohexylamin platinum (IV)] Ann Oncol1994; 5 (Suppl 5): 1268. Bunn PA Jr. Review of therapeutic trials of carboplatin in lungcancer. Semin Oncol 1989; 16 (Suppl 5): 27-33.Received 5 February 1997; accepted 22 April 1997.References1. Cancer Statistics, 1992. CA 1992; 42: 19-38.2. Kris M, Cohen E, Gralla R. An analysis of 134 phase II trials innon-small cell lung cancer IV. Toronto: World Conference on LungCancer 1985; 39.3. Giandomenico CM, Abrams MJ, Murrer BA et al. Synthesis andCorrespondence to.Dr. Ian JudsonCRC Centre for Cancer TherapeuticsThe Institute of Cancer Research15, Cotswold RoadSutton, Surrey, SM2 5NGUK

Phase II trial of the oral platinum complex JM216 in non-small-cell lung cancer: An EORTC early clinical studies group investigation

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Phase II trial of the oral platinum complex JM216 in non-small-cell lung cancer: An EORTC early clinical studies group investigation

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