GEMCITABINE, IFOSFAMIDE, CISPLATIN (GIP) FOR THE TREATMENT OF ADVANCED NON-SMALL CELL LUNG CANCER: A PHASE II STUDY OF THE ITALIAN ONCOLOGY GROUP FOR CLINICAL RESEARCH (GOIRC) C. BONI 1 * , G. BISAGNI 1 , L. SAVOLDI 1 , G. MORETTI 1 , E. RONDINI 1 , M. SASSI 1 , A. ZADRO 1 , T. DE PAS 2 , V. FRANCIOSI 3 , A. PAZZOLA 4 , R. VIGNOLI 5 , M.C. BANZI 1 and V. PAJETTA 1 1 Medical Oncology Service, Arcispedale S. Maria Nuova, Reggio Emilia, Italy 2 Medical Oncology Division, European Institute of Oncology, Milan, Italy 3 Medical Oncology Division, Ospedale Maggiore, Parma, Italy 4 Medical Oncology Service, Ospedale Civile, Sassari, Italy 5 Internal Medicine Division, Ospedale S. Anna, Castelnuovo ne’ Monti, Reggio Emilia, Italy The purpose of this study was to evaluate the activity and the toxicity of the combination of gemcitabine with ifosf- amide and cisplatin (GIP) in chemonaive patients with ad- vanced non small cell lung cancer (NSCLC). Eighty chemona- ive patients with Stage IIIB-IV NSCLC were treated with the combination of gemcitabine 1 g/m 2 on Days 1 and 8, ifosf- amide 2 g/m 2 on Day 1 and cisplatin 80 mg/m 2 on Day 2. Cycles were administered on an outpatient basis every 3 weeks. Hematologic toxicity was the main side effect; Grade III-IV thrombocytopenia was observed in 54 (67%) patients and Grade III-IV leucopenia in 44 (55%) patients, with 4 episodes of febrile neutropenia and 1 toxic death. Thirteen patients received platelet transfusions and 38 were trans- fused with packed red cells. All patients were evaluable for response. The overall response rate was 54% (95% confidence interval 43 to 65%) with 1 complete response. In patients with Stage IIIB and IV disease, response rates were 58% and 52%, respectively. Median time to progression was 40 weeks (range 0 –114) and median overall survival was 12 months (16.6 months for stage IIIB and 10.4 months for stage IV). Median and minimum follow-up were 19 and 12 months, respectively. The GIP combination shows a response rate and overall survival of clinical interest. Hematologic toxicity was the main toxic effect, especially in patients with low performance status. This regimen will be tested in a Phase III randomized trial. Int. J. Cancer 87:724 –727, 2000. © 2000 Wiley-Liss, Inc. Historically, NSCLC has been considered a chemoresistant dis- ease, although significant activity (response rates 15%) has been observed with single-agent chemotherapy, such as cisplatin, vin- desine, mitomycin, ifosfamide and recently with taxanes, gemcit- abine and vinorelbine (Johnson, 1990; Depierre et al., 1991; Anderson et al., 1994; Hainsworth et al., 1995; Fossella et al., 1994). In 1995, a meta-analysis showed a significant improvement in survival for cisplatin-containing regimens compared with the best supportive care and platinum-containing regimens still remain the reference treatment (Non Small Cell Lung Cancer Cooperative Group, 1995). Gemcitabine (2'2'-difluorodeoxycytidine) is a novel nucleoside analog that is incorporated into DNA as a fraudulent base. This metabolite (difluorodeoxycytydine triphosphate) inhibits the activity of DNA polymerases responsible for DNA repair and synthesis, and is also a potent inhibitor of the enzyme, ribonucleotide reductase (Huang et al., 1991; Plunkett et al., 1989). These characteristics suggest that gemcitabine may be a good candidate for combination with other cytotoxic drugs, particularly those that cause DNA dam- age. In preclinical studies, gemcitabine has demonstrated impor- tant antitumor activity in many human tumor xenografts, including lung cancer. Moreover, experimental data, both in vitro and in vivo, suggest that the gemcitabine-cisplatin combination, in close sequence or simultaneous exposure, should interact synergistically (Braakhuis et al., 1994; Fujita et al., 1994; Peters et al., 1995). Phase II studies have demonstrated that gemcitabine has mild side effects and is active against NSCLC with a response rate of approximately 20% in previously untreated patients (Anderson et al., 1994; Abratt et al., 1994). This level of activity is comparable to that seen with the most active established single agents such as, cisplatin, ifosfamide and mitomycin-C. The combination of gemcitabine and cisplatin has recently shown a very high activity in a Phase II trial in patients with Stage IV NSCLC, with a response rate of 54% and a median survival of 14 months. Side effects were modest and included: Grade 3– 4 thrombocytopenia in 52% of patients, Grade 3– 4 neutropenia in 36% of patients and no toxic deaths (Crino ` et al., 1997). In a subsequent Phase III trial, the same group obtained a response rate of 38% with a median survival of 8.6 months (Crino ` et al., 1999). Data from 6 studies that evaluated the influence of Gemcitabine and Cisplatin schedule showed that the combination with Cisplatin given sequentially on day 2, 24 hr after Gemcitabine, was associ- ated with a better response rate and a better survival compared to the schedule with Cisplatin administered concomitantly with Gem- citabine on day 1 (Shepherd et al., 1998). In preclinical studies, ifosfamide showed interesting activity against NSCLC human xenografts (Berger et al., 1990). Used as a single agent in patients with advanced NSCLC, ifosfamide has demonstrated activity, with a response rate of 20 to 25% and median survival of 9 months; thus, it is considered one of the most active drugs against this tumor (Johnson, 1990; Herbst et al., 1997). The combination of ifosfamide and cisplatin has shown syner- gistic activity in experimental models (Goldin, 1982). Moreover, in Phase III studies of chemotherapy in NSCLC, the best results have been obtained with ifosfamide-containing regimens (Crino ` et al., 1995; Sculier et al., 1998). Based on these premises, we designed a Phase II trial to evaluate the activity and toxicity of a new three-drug combination regimen that consisted of gemcitabine, ifosfamide and cisplatin (GIP) in chemonaive patients with Stage IIIB/IV NSCLC. MATERIAL AND METHODS Eligibility Patients with histologically or cytologically confirmed unresect- able Stage IIIB or metastatic (Stage IV) NSCLC with the presence of at least one measurable or evaluable lesion were eligible for the study. Patients did not receive prior chemotherapy. Previous pal- liative radiotherapy to symptomatic metastases was allowed, pro- vided that these lesions were not considered for tumor response assessment. Criteria for entry into the trial also included ECOG performance status (PS) 2, age 75 years, WBC count 4,000/ *Correspondence to: Corrado Boni, Medical Oncology Service, Spal- lanzani Hospital, Arcispedale S. Maria Nuova, Viale Umberto I, 50, 42100 Reggio Emilia, Italy. Fax: 0039 0522 296854. E-mail: boni.corrado@asmn.re.it Received 11 February 2000; Revised 3 April 2000; Accepted 6 April 2000 Int. J. Cancer: 87, 724 –727 (2000) © 2000 Wiley-Liss, Inc. Publication of the International Union Against Cancer