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A Phase I Trial of the Oral Platinum Analogue JM216 with Concomitant Radiotherapy in Advanced Malignancies of the Chest

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Abstract

JM216 is an orally administered platinumanalogue. We undertook this study todetermine the maximally tolerated dose(MTD) of JM216 when administered withconcomitant radiotherapy to the chest(200 cGy daily, 5×/week) in patients withlocoregionally advanced non-small cell lung(NSCLC) or esophageal cancer. Patientswere excluded for inadequate bone marrowreserve, prior radiotherapy to the primarytumor or previous treatment with platinumdrugs. A dose-limiting toxicity (DLT) wasdefined using the National Cancer Institute(NCI) Common Toxicity Criteria (CTC) andconsisted of grade ≥2 renal, hepatic,cardiac, or pulmonary toxicity or grade ≥3hematologic, neurological, orgastrointestinal toxicity. A total of 23patients were registered; two neverreceived treatment and are excluded fromanalyses. Six patients were treated at adose of 30 mg/m2/day for 5 days withtwo grade 2 DLT's: cough (1 pt) andelevated trans-aminases (1 pt). Sevenevaluable patients were treated at60 mg/m2/day and seven experiencedgrade 3 or 4 toxicity, five related tomyelosuppression. The dose was thenreduced to 45 mg/m2/d. Eight patientswere evaluable for toxicity, of which 5experienced DLT: myelosuppression (3 pts),esophagitis (2 pts), dyspnea (1 pt), andelevated creatinine (1 pt). Fourteenpatients were evaluable for efficacy, ofwhich 6 had an objective response,including one complete response. Therecommended phase II dose of JM216 withconcurrent radiation therapy is30 mg/m2/d for 5 days. The major DLTis myelosuppression with only limitedincreased toxicity within the field ofradiation. This conceivably may limit theuse of JM216 as a radiation sensitizer.

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REFERENCES

  1. Vokes EE, Weichselbaum RR: Concomitant chemoradiotherapy: rationale and clinical experience in patients with solid tumors. J Clin Oncol 8: 911–934, 1990

    Google Scholar 

  2. Gordon GS, Vokes EE: Chemoradiation for locally advanced, unresectable NSCLC. New standard of care, emerging strategies. Oncology (Huntingt) 13: 1075–1088, 1999

    Google Scholar 

  3. Ginsberg RT, Vokes EE, Raben A: Non-small cell lung cancer. In: Devita VT, Hellman S, Rosenberg, SA (eds) Cancer: Principles and Practice of Oncology 2000 (in press).

  4. ASCO: Clinical practice guidelines for the treatment of unresectable non-small-cell lung cancer. J Clin Oncol 15: 2996–3018, 1997

    Google Scholar 

  5. Dillman RO, Herndon J, Seagren SL, Eaton WL, Jr, Green MR: Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of cancer and leukemia group B (CALGB) 8433 trial. J Natl Cancer Inst 88: 1210–2115, 1996

    Google Scholar 

  6. Sause W, Kolesar P, Taylor SI, Johnson D, Livingston R, Komaki R, Emami B, Curran W, Jr, Byhardt R, Dar AR, Turrisi A, 3rd: Final results of phase III trial in regionally advanced unresectable non-small cell lung cancer: Radiation Therapy Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. Chest 117: 358–364, 2000

    Google Scholar 

  7. Albain KS, Rusch VW, Crowley JJ, Rice TW, Turrisi AT, 3rd, Weick JK, Lonchyna VA, Presant CA, McKenna RJ, Gandara DR, Fosmire H, Taylor SA, Stelzer KJ, Beasly KR, Livingston RB: Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-smallcell lung cancer: mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol 13: 1880–1892, 1995

    Google Scholar 

  8. Schaake-Koning C, Maat B, van Houtte P, van den Bogaert W, Dalesio O, Kirkpatrick A, Bartelink H: Radiotherapy combined with low-dose cis-diammine dichloroplatinum (II) (CDDP) in inoperable nonmetastatic non-small cell lung cancer (NSCLC): a randomized three arm phase II study of the EORTC Lung Cancer and Radiotherapy Cooperative Groups. Int J Radiat Oncol Biol Phys 19: 967–972, 1990

    Google Scholar 

  9. Schaake-Koning C, van den Bogaert W, Dalesio O, Festen J, Hoogenhout J, van Houtte P, Kirkpatrick A, Koolen M, Maat B, Nijs A: Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. N Engl J Med 326: 524–530, 1992

    Google Scholar 

  10. Furuse K, Fukuoka M, Kawahara M, Nishikawa H, Takada Y, Kudoh S, Katagami N, Ariyoshi Y: Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol 17: 2692–2699, 1999

    Google Scholar 

  11. Curran WJ, Scott C, Langer C, Komaki R, Lee JS, Hauser S, Movsas B, Wasserman TH, Rosenthal S et al: Phase III comparision of sequential vs concurrent chemoradiation for patients (Pts) with unresected stage III non-small cell lung cancer (NSCLC): intitial report of radiation therapy oncology group (RTOG) 9410. Proc ASCO 1891, 2000

  12. Gandara DR, Lovato LC, Albain KS, Leigh B, Lara PN, Crowley JJ et al: Prolonged survival in pathologic stage IIIB nonsmall cell lung cancer (NSCLC) with concurrent chemoradiotherapy followed by consolidation docetaxel: A phase II study (S9504) of the southwest oncology group (SWOG). Proc ASCO 1916, 2000

  13. Herskovic A, Martz K, al-Sarraf M, Leichman L, Brindle J, Vaitkevicius V, Cooper J, Byhardt R, Davis L, Emami B: Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med 326: 1593–1598, 1992

    Google Scholar 

  14. al-Sarraf M, Martz K, Herskovic A, Leichman L, Brindle JS, Vaitkevicius VK, Cooper J, Byhardt R, Davis L, Emami B: Progress report of combined chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer: an intergroup study. J Clin Oncol 15: 277–284, 1997

    Google Scholar 

  15. Walsh TN, Noonan N, Hollywood D, Kelly A, Keeling N, Hennessy TP: A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 335: 462–467, 1996

    Google Scholar 

  16. Heath EI, Burtness BA, Heitmiller RF, Salem R, Kleinberg L: Phase II evaluation of preoperative chemoradiation and postoperative adjuvant chemotherapy for squamous cell and adenocarcinoma of the esophagus. J Clin Oncol 18: 868–876, 2000

    Google Scholar 

  17. Sorenson CM, Eastman A: Mechanism of cis-diamminedichloroplatinum (II)-induced cytotoxicity: role of G2 arrest and DNA double-strand breaks. Cancer Res 48: 4484–4488, 1988

    Google Scholar 

  18. Begg AC, van der Kolk PJ, Dewit L, Bartelink H: Radiosensitization by cisplatin of RIF1 tumour cells in vitro. Int J Radiat Biol Relat Stud Phys Chem Med 50: 871–884, 1986

    Google Scholar 

  19. Yang L, Douple EB, O'Hara JA, Crabtree RA, Eastman A: Enhanced radiation-induced cell killing by carboplatin in cells of repair-proficient and repair-deficient cell lines. Radiat Res 144: 230–236, 1995

    Google Scholar 

  20. Rose WC, Crosswell AR, Schurig JE, Casazza AM: Preclinical antitumor activity of orally administered platinum (IV) complexes. Cancer Chemother Pharmacol 32: 197–203, 1993

    Google Scholar 

  21. Kelland LR, Abel G, McKeage MJ, Jones M, Goddard PM, Valenti M, Murrer BA, Harrap KR: Preclinical antitumor evaluation of bis-acetato-ammine-dichloro-cyclohexylamine platinum (IV): an orally active platinum drug. Cancer Res 53: 2581–2586, 1993

    Google Scholar 

  22. O'Neill CF, Koberle B, Masters JR, Kelland LR: Gene-specific repair of Pt/DNA lesions and induction of apoptosis by the oral platinum drug JM216 in three human ovarian carcinoma cell lines sensitive and resistant to cisplatin. Br J Cancer 81: 1294–1303, 1999

    Google Scholar 

  23. McKeage MJ, Raynaud F, Ward J, Berry C, O'Dell D, Kelland LR, Murrer B, Santabarabara P, Harrap KR, Judson IR: Phase I and pharmacokinetic study of an oral platinum complex given daily for 5 days in patients with cancer. J Clin Oncol 15: 2691–2700, 1997

    Google Scholar 

  24. Amorino GP, Freeman ML, Carbone DP, Lebwohl DE, Choy H: Radiopotentiation by the oral platinum agent, JM216: role of repair inhibition. Int J Radiat Oncol Biol Phys 44: 399–405, 1999

    Google Scholar 

  25. van de Vaart PJ, Klaren HM, Hofland I, Begg AC: Oral platinum analogue JM216, a radiosensitizer in oxic murine cells. Int J Radiat Biol 72: 675–683, 1997

    Google Scholar 

  26. McKeage MJ, Mistry P, Ward J, Boxall FE, Loh S, O'Neill C, Ellis P, Kelland LR, Morgan SE, Murrer B: A phase I and pharmacology study of an oral platinum complex, JM216: dosedependent pharmacokinetics with single-dose administration. Cancer Chemother Pharmacol 36: 451–458, 1995

    Google Scholar 

  27. Beale P, Raynaud F, Hanwell J, Berry C, Moore S, Odell D, Judson I: Phase I study of oral JM216 given twice daily. Cancer Chemother Pharmacol 42: 142–148, 1998

    Google Scholar 

  28. Sessa C, Minoia C, Ronchi A, Zucchetti M, Bauer J, Borner M, de Jong J, Pagani O, Renard J, Weil C, D'Incalci M: Phase I clinical and pharmacokinetic study of the oral platinum analogue JM216 given daily for 14 days. Ann Oncol 9: 1315–1322, 1998

    Google Scholar 

  29. DeMario MD, Ratain MJ, Vogelzang NJ, Mani S, Vokes EE, Fleming GF, Melton K, Johnson S, Benner S, Lebwohl D: A phase I study of oral uracil/ftorafur (UFT) plus leucovorin and bis-acetato-ammine-dichloro-cyclohexylamin e-platinum IV (JM-216) each given over 14 days every 28 days. Cancer Chemother Pharmacol 43: 385–388, 1999

    Google Scholar 

  30. Fokkema E, de Vries EG, Meijer S, Groen HJ: Lack of nephrotoxicity of new oral platinum drug JM216 in lung cancer patients. Cancer Chemother Pharmacol 45: 89–92, 2000

    Google Scholar 

  31. Judson I, Cerny T, Epelbaum R, Dunlop D, Smyth J, Schaefer B, Roelvink M, Kaplan S, Hanauske A: Phase II trial of the oral platinum complex JM216 in non-small-cell lung cancer: an EORTC early clinical studies group investigation. Ann Oncol 8: 604–606, 1997

    Google Scholar 

  32. Fokkema E, Groen HJ, Bauer J, Uges DR, Weil C, Smith IE: Phase II study of oral platinum drug JM216 as first-line treatment in patients with small-cell lung cancer. J Clin Oncol 17: 3822–3827, 1999

    Google Scholar 

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Authors and Affiliations

  1. Section of Hematology/Oncology, University of Chicago, IL

    Christopher M. George, Ann M. Mauer, Stuart A. Krauss, Philip C. Hoffman, Charles M. Rudin, Livia Szeto & Everett E. Vokes

  2. Section of Radiation & Cellular Oncology, University of Chicago, IL, U.S.A.

    Dan J. Haraf & Everett E. Vokes

  3. Cancer Research Center, University of Chicago, Chicago, IL, U.S.A.

    Dan J. Haraf, Ann M. Mauer, Charles M. Rudin & Everett E. Vokes

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  1. Christopher M. George
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  2. Dan J. Haraf
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  8. Everett E. Vokes
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George, C.M., Haraf, D.J., Mauer, A.M. et al. A Phase I Trial of the Oral Platinum Analogue JM216 with Concomitant Radiotherapy in Advanced Malignancies of the Chest. Invest New Drugs 19, 303–310 (2001). https://doi.org/10.1023/A:1010653508700

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