A PHASE I-II STUDY OF DOCETAXEL-IFOSFAMIDE-CISPLATIN (DIP) COMBINATION CHEMOTHERAPY REGIMEN IN ADVANCED NONSMALL CELL LUNG CANCER Christos KOSMAS 1 * , Nicolas B. TSAVARIS 2 , Thomas MAKATSORIS 3 , Adimchi ONYENADUM 3 , Maria VADIAKA 2 , Niki STAVROYIANNI 2 , Evangelos SEPSAS 4 , Dimitris DIMITROPOULOS 3 , Sofia ROKANA 1 and Haralambos P. KALOFONOS 3 1 Department of Medicine, Medical Oncology Unit, Helena-Venizelou Hospital, Athens, Greece 2 Medical Oncology Unit, Laikon General Hospital, Athens University School of Medicine, Athens, Greece 3 Department of Medicine/Oncology, Patras University School of Medicine, Rio, Patras, Greece 4 Department of Thoracic Surgery, Chest Diseases Hospital of Athens, Athens, Greece In an attempt to develop more effective chemotherapy regimens in advanced nonsmall cell lung cancer (NSCLC), we evaluated docetaxel-ifosfamide-cisplatin (DIP) based on our previous experience with paclitaxel-ifosfamide-cisplatin. Pa- tients with advanced NSCLC (stages III-IV), WHO-PS<2, no prior chemotherapy and unimpaired hematopoietic and or- gan function were eligible. Chemotherapy was administered in successive dose levels (DLs) and included docetaxel (80 – 100 mg/m 2 day 1), ifosfamide (4 –5 g/m 2 ) and cisplatin (80 – 100 mg/m 2 ), both divided over days 1 and 2 every 21 days. G-CSF (lenograstin) was administered from days 4 –13. Fifty- five patients were accrued (phase I: 15; phase II: 40) and all are evaluable for response and toxicity: median age  58 (40 –72); PS  1 (0 –2); gender  48 males, 7 females; stages IIIA  8, IIIB  19, IV  28; and histologies were adenocar- cinoma (29), squamous (20), large cell (6). Metastatic sites at diagnosis included lymph nodes (33), bone (8), liver (6), brain (6), lung nodules (9), adrenals (7) and soft tissue (1). The dose-limiting toxicity (DLT) was reached at DL4 (Docetaxel: 100 mg/m 2 -Ifosfamide: 5 g/m 2 -Cisplatin: 100 mg/m 2 ) consist- ing of 2 cases of febrile neutropenia (FN), and DL3 (Do- cetaxel: 100 mg/m 2 -Ifosfamide: 5 g/m 2 -Cisplatin: 80 mg/m 2 ) was considered as the maximum tolerated dose (MTD) and recommended for further phase II testing. Among evaluable patients in phase II, 31/46 (67%; CI  54 – 81%) responded; 4 were complete responses, 27 partial responses, 12 with sta- ble disease and 3 with progressive disease. The median re- sponse duration was 7 months (2–21), median time to pro- gression (TTP) 8 months (1–23) and median overall survival (OS) 13 months (2–23). The 1-year survival was 57%. Grade (Gr) 3/4 toxicities included neutropenia 39/46 with 27 devel- oping Gr4 (<7 days) and 20% FN managed successfully with broad-spectrum antibiotics, thrombocytopenia Gr3 3/46-Gr4 1/46, no Gr3 neuropathy, Gr1-2 CNS toxicity in 12, no renal toxicity, 15 Gr2 myalgias, 17 Gr2 diarrhea and 10 Gr3 vom- iting. In the present phase I-II study, DIP appears highly active and tolerable in advanced NSCLC in the outpatient setting. Randomized comparisons to current standard 2-drug regimens will be warranted. © 2002 Wiley-Liss, Inc. Key words: docetaxel; ifosfamide; cisplatin; chemotherapy; nonsmall cell lung cancer Nonsmall cell lung cancer (NSCLC) has been considered tradi- tionally refractory to cytotoxic chemotherapy. Cisplatin-based che- motherapy regimens have produced a small but finite chance of survival prolongation in a large meta-analysis of randomized clin- ical trials. 1 Introduction of newer agents with different mecha- nisms of antineoplatic activity have provided the opportunity to devise combinations of these drugs with platinum compounds. Docetaxel (Taxotere) has demonstrated a broad spectrum of activity against a variety of advanced solid tumors. The combination of another taxane, paclitaxel, with either cis- platin or carboplatin has shown encouraging activity in patients with advanced NSCLC, and randomized comparisons against stan- dard previous generation cisplatin-based regimens with etoposide or teniposide have revealed its superiority. 2,3 Moreover, the prior popular 3-drug combination of mitomycin-ifosfamide-ciplatin (MIP) has demonstrated improved response rates and survival prolongation when compared to the early ‘90s standard: the cis- platin-etoposide regimen in a large cooperative European study. 4 However, it is not yet known whether triple drug combinations would be superior to current 2-drug regimens incorporating novel agents, such as paclitaxel, docetaxel, gemcitabine, vinorelbine in combination with platinum analogues. Ifosfamide, an oxazophos- phorine alkylating agent with significant activity, as a single agent, in NSCLC has been successfully incorporated in the MIP regimen, yielding satisfactory activity and tolerability. 5,6 Combination of ifosfamide with paclitaxel and cisplatin (PIC) has been carried out in a previous phase I study by our group, and it has been demon- strated that high individual doses of each drug can be achieved, aided by G-CSF with acceptable toxicity in the outpatient setting. 7 Based on these, we demonstrated very high activity, prolonged TTP and survival in a phase II study of PIC in advanced NSCLC. 8 Docetaxel very likely represents the only new drug with signif- icant single-agent activity in cisplatin-relapsed/refractory NSCLC (17% RR). 9 Building on this background and the potentially dif- ferent toxicity profiles between docetaxel and paclitaxel when combined with other agents, in our current study, we aimed to test the tolerability and activity of a novel regimen (DIP), incorporat- ing docetaxel instead of paclitaxel into the ifosfamide-ciplatin combination, and conducted a novel phase I-II study in patients with advanced NSCLC. MATERIAL AND METHODS Patient selection Patients with histologically confirmed advanced NSCLC, stage IIIA (bulky), IIIB and IV were candidates for our study. Eligibility included (i) histologically confirmed NSCLC not curable by sur- gery and/or radiotherapy; (ii) WHO performance status 2; (iii) life expectancy 3 months; (iv) adequate hematopoietic (ANC  1,500/l, PLT  100,000/l), liver [bilirubin  1.5 mg/dl, AST/ ALT  2 upper normal limit (nl), unless caused by tumor and serum albumin 3.0 g/dl] and renal function (BUN and creati- nine  1.5 nl; nl = 1.5 mg/dl in our laboratory or creatinine clearance 50 ml/min); (v) no previous chemotherapy; (vi) ab- sence of active coronary artery disease (in the form of unstable angina or myocardial infarction over the last 12 months), unstable diabetes mellitus or peripheral neuropathy grade 2 by the NCI- Common Toxicity Criteria (CTC); (vii) no prior irradiation to areas *Correspondence to: Consultant Medical Oncologist, Department of Medicine, Medical Oncology Unit, Helena-Venizelou Hospital, 21 Apol- loniou Street, GR-163 41 Athens, Greece. Fax: +301-996-2917. E-mail: ckosm@ath.forthnet.gr Received 16 July 2001; Revised 12 September 2001; Accepted 5 Octo- ber 2001 Published online 29 November 2001 Int. J. Cancer: 98, 141–147 (2002) © 2002 Wiley-Liss, Inc. DOI 10.1002/ijc.10162 Publication of the International Union Against Cancer