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During the conference, there were a number of presentations on new, phase I combination data, which are summarized below.
Irinotecan plus capecitabine. Not surprisingly, oncologists are keen to determine whether similar results can be achieved when irinotecan is administered in combination with oral fluoropyrimidines. New data from a phase 1/2 trial was initiated to identify the recommended dose for further clinical development and to assess the safety profile of the combination.
Capecitabine was administered on days 1-14 and 22-36 at doses of 1000 or 1250 mg/m2 twice daily, and irinotecan was administered as a weekly 30-minute iv infusion for 6 weeks at doses of 70 and 80 mg/m2. This cycle of treatment was repeated every 50 days. All patients had metastatic colorectal cancer, measurable disease, and had received no prior treatment for metastatic disease. The dose levels and patient recruitment to each level are shown in Table 3.
Dose Level Capecitabine (days 1-14 and 22-36, mg/m2 oral, twice daily) Irinotecan (mg/m2 iv weekly x 6) No. of patients No. of cycles 1 1000 70 3 7 2 1250 70 8 9 3 1250 80 6 13
4 1250 90 -- --
Dr. Vanhoefer presented data from 17 patients treated for 39 cycles, which show that the combination is feasible. Among these patients, there were only 2 cases of grade 3 or 4 neutropenia (grade 3 at the second-dose level, grade 4 at the third-dose level). Both of these events occurred in the first treatment cycle, and no further grade 3 or 4 neutropenia was observed in subsequent cycles. The principal grade 3 or 4 nonhematologic adverse event was diarrhea, which occurred in 3 patients (2 grade 3 at the third-dose level and 1 grade 4 at the second-dose level). Only 1 patient experienced hand-foot syndrome (grade 2 at the third-dose level). The maximum tolerated dose was defined as dose level 3. Preliminary efficacy data from the study are encouraging, with a high proportion of complete and partial responses. Data for 6 patients are not yet mature and therapy is ongoing.
Dr. Vanhoefer concluded that capecitabine plus irinotecan combination therapy is a feasible new treatment option. The recommended dose level for further evaluation is capecitabine 1250 mg/m2 twice daily, administered on days 1-14 and 22-36 in combination with weekly irinotecan 70 mg/m2 administered for 6 weeks, repeated every 50 days. This regimen is currently being evaluated in an extended phase I/II study, and further investigation in phase III trials is planned.
Irinotecan plus UFT/LV. Irinotecan has also been investigated in combination with UFT/LV as first-line treatment for advanced or metastatic colorectal cancer. Results of a phase I, dose-escalation trial involving 20 patients were summarized in a talk on the second day of the conference. A total of 97 treatment cycles have been administered, and the dose-limiting toxicities were diarrhea and febrile neutropenia (2 patients each). The most common grade 3/4 toxicities were nausea (16%), fatigue/lethargy (19%), diarrhea (16%), and neutropenia (9%).
The recommended dose has been identified as UFT 250 mg/m2/day plus LV 90 mg/day (both administered as 3 divided doses, days 1-14) in combination with irinotecan 250 mg/m2 on day 1, every 3 weeks. Preliminary efficacy results from 14 patients show a response rate of 29% (1 complete response, 3 partial responses). Four additional patients were not evaluable for efficacy because of early toxicity. Following identification of the recommended dose for this combination, a phase II extension of the study is being conducted to further assess the efficacy and safety of this regimen. So far, 20 patients have been treated at the recommended dose.
Irinotecan plus raltitrexed. Another agent investigated in combination with a number of therapies and discussed by Dr. Twelves is raltitrexed, a thymidylate synthase inhibitor. However, results reported to date for this combination in a range of settings are disappointing. In a phase I combination study in heavily pretreated patients with colorectal cancer, a regimen of irinotecan 180 mg/m2 on day 1 followed by raltitrexed 2 mg/m2 on day 2, repeated every 2 weeks, demonstrated no antitumor activity. There were no objective responses and the median TTP was just 13 weeks. The investigators suggested that further evaluation in less heavily pretreated patients was warranted.
Two additional trials of the combination as first-line treatment demonstrated promising antitumor activity (53% and 30%, respectively), but significant toxicity was observed in both trials.[24,25] Toxic deaths occurred in 5% of patients treated in the first study, with a further 38% of patients requiring dose reduction, and more than three quarters of patients in the second trial experienced grade 3/4 toxicity. Further evaluation using lower doses of these 2 drugs is planned.
Oxaliplatin plus capecitabine. Preclinical studies have shown that the combination of fluoropyrimidines and oxaliplatin can partially overcome clinical resistance to fluoropyrimidines. Therefore, a phase I, dose-escalation trial was conducted in 4 centers in the UK and Spain to investigate the combination of capecitabine and oxaliplatin. The study included 23 patients with advanced/metastatic solid tumors resistant to standard chemotherapeutic regimens, and the latest results were presented by Professor Díaz-Rubio in Barcelona.
Oxaliplatin was administered at a fixed dose of 130 mg/m2 on day 1 of each 21-day cycle and capecitabine was administered at a starting dose of 500 mg/m2 twice daily, days 1-14. The dose-limiting toxicity was diarrhea (grade 3 in 2 patients [1 patient each at capecitabine 1000 and 1250 mg/m2 twice daily] and grade 4 in 1 patient [capecitabine 1250 mg/m2 twice daily]). The investigators identified a regimen of oxaliplatin 130 mg/m2 combined with capecitabine 1000 mg/m2 twice daily, days 1-14, administered as a 3-weekly cycle, as the most appropriate schedule for further development. The combination was well tolerated at this dose, and most toxic effects were of mild to moderate intensity.
Professor Díaz-Rubio highlighted the efficacy results obtained in a subgroup of 9 patients with pretreated colorectal cancer (including prior irinotecan in 4 patients). Five of these patients achieved partial responses and, in 3 of them, disease was stabilized. These promising results have led to the initiation of a phase II trial to further evaluate capecitabine/oxaliplatin combination therapy.
Oxaliplatin plus UFT/LV. Oxaliplatin has also been investigated in combination with UFT/LV. The study was conducted in Spain and used a slightly different schedule from the capecitabine trial. The treatment regimen consisted of oxaliplatin 100 mg/m2 on days 1 and 14, oral UFT 390 mg/m2 for 14 days, and LV 250 mg/m2 as a 2-hour infusion on day 1 followed by oral LV 7.5 mg every 12 hours for 14 days. Treatment was repeated every 28 days. Grade 3/4 toxicities were quite common in the first 2 cycles (diarrhea 54%, nausea/vomiting 23%), and consequently the UFT dose was reduced from 390 mg/m2 to 300 mg/m2. At the lower dose, grade 3/4 diarrhea occurred in 18% of patients and grade 3/4 nausea/vomiting occurred in 9% of patients.
Oxaliplatin plus raltitrexed. Raltitrexed has shown more promise as a combination partner for oxaliplatin than irinotecan, and the most recent data were reviewed by Dr. Twelves. The efficacy of raltitrexed and oxaliplatin, administered at their full doses, has been evaluated in combination trials, with encouraging activity noted in patients with advanced colorectal cancer. In a phase II trial involving 71 patients with untreated metastatic colorectal cancer, 29 patients achieved objective tumor responses (1 complete response, 38 partial responses). The median TTP was 6.3 months and median survival has not yet been reached.
It is still too early to select the optimal combination, commented Dr. Twelves, but the numerous phase I/II studies that have been reported recently show that several combination regimens are feasible and active. If 5-FU/irinotecan combination therapy becomes the gold standard for first-line treatment of colorectal cancer, it will be interesting to see if we can improve therapy in terms of efficacy, safety, and convenience by replacing 5-FU with an effective oral fluoropyrimidine.