A four-arm, randomized, multicenter phase II trial of oxaliplatin combined with varying schedules of 5-fluorouracil as first-line therapy in previously untreated advanced colorectal cancer.

BACKGROUND: Oxaliplatin combined with 5-fluorouracil (5-FU), with or without leucovorin (LV), is effective and well tolerated for first-line therapy of advanced colorectal cancer (CRC). However, there is no consensus as to which oxaliplatin/5-FU-containing regimen is superior in the first-line setting. This randomized, multicenter phase II trial was designed to evaluate and compare the efficacy of 4 different oxaliplatin/5-FU regimens. PATIENTS AND METHODS: Patients with previously untreated metastatic CRC (mCRC; n = 129) were randomized to 1 of 4 treatment regimens: (1) continuous 5-FU infusion plus oxaliplatin (n = 23); (2) weekly 5-FU bolus with LV plus oxaliplatin (n = 40); (3) oxaliplatin with 2-day infusion 5-FU/LV (FOLFOX4, n = 41); and (4) chronomodulated 5-FU plus oxaliplatin (n = 25). RESULTS: Overall response rates, after expert assessment, ranged from 24% to 34%, and median progression-free survival (PFS) ranged from 6 months to 8 months. Although no significant differences in efficacy were detected in pairwise comparisons of the 4 different regimens, patients randomized to FOLFOX4 had the highest response rate and longest PFS. The FOLFOX4 regimen was also associated with the lowest incidence of severe (grade 3/4) toxicity, with the exception of cumulative peripheral neurotoxicity. CONCLUSION: This randomized phase II trial provides evidence that oxaliplatin/5-FU regimens are effective and well tolerated for first-line therapy of previously untreated mCRC. The FOLFOX regimens are now an established standard for CRC.

Phase II trial of KW2189 in patients with advanced malignant melanoma.

KW-2189, a semisynthetic duocarmycine antibiotic has been shown to exert antiproliferative effects against human tumor cell lines in vitro and animal tumor models in vivo. Phase I studies identified myelosuppression as the most noteworthy adverse effect. Presented are two concurrent phase II studies assessing the antitumor and toxicity profile of KW-2189 in metastatic melanoma patients. One of the studies accrued patients with a history of prior melanoma therapy and the other accrued patients without a history of prior melanoma therapy. KW-2189 was administered at 0.4 mg/m2 to previously treated patients and 0.5 mg/m2 to the previously untreated. Treatment was administered intravenously on day 1 of a 6-week cycle. Thirty previously untreated and 15 previously treated patients were accrued. The toxicity profiles of the both groups of patients were similar. Of the 15 previously treated patients, 8 completed once cycle of treatment, 2 completed 2 cycles, and 5 completed 3 cycles. Dose modification for neutropenia/ thrombocytopenia was necessary in six patients. Among the previously untreated cohort (30 patients), 16 completed 1 cycle, 5 completed 2 cycles, 4 completed 3 cycles, 3 completed 4 cycles, and 2 completed 6 cycles. Doses were modified (neutropenia or thrombocytopenia) in 11 patients. None of the 15 previously treated patients responded to therapy. Four patients remained stable during two cycles. Five of the previously untreated patients achieved a partial remission/regression. Response duration ranged from 2.8 to 16.6 months. Overall objective response rate was 17%. Regarding survival, one previously treated patient is still alive 2.9 years after study entry, and three previously untreated patients are still alive 1.6, 2.3, and 2.9 years after study entry. The 1-year survival rate for previously treated patients is 27% and for the untreated patients is 23%. In summary, the lack of significant antitumor activity of KW-2189 and its associated toxicity suggest that further testing of this regimen in patients with stage IV melanoma is not warranted.

A phase I clinical and pharmacokinetic study of CS-682 administered orally in advanced malignant solid tumors.

CS-682 (1-(2-C-cyano-2-deoxy-beta-D-arabino-pentofuranosyl)-N4-palmitoylcytosine) is a novel orally administered 2'-deoxycytidine-type antimetabolite, which has a wide spectrum of antitumor activity in human tumor xenograft models. We conducted a phase I study to define the toxicity, pharmacokinetics and antitumor activity of CS-682 in patients with advanced solid tumors. Forty patients were enrolled to receive escalating doses of CS-682. CS-682 was given orally, once daily three times a week (Monday, Wednesday and Friday), for four weeks consecutively, followed by a two-week rest period. Twenty-two men and 18 women, median age 63.5 (range 31 to 82) were treated. The most common tumor type was colorectal cancer with 15 patients. Others tumors occurring in 3 or more patients included prostate, breast and lung carcinomas. Sixty percent of the patients had received greater than 2 prior chemotherapy programs. Patients have been treated at each of the following dose levels (mg/m2/day): 1.5, 12, 20, 25, 30, 50, 67, 90, 120, 160 and 220. Non hematologic toxicities grade 3 [NCI Common Toxicity Criteria (version 2.0)] related to treatment included nausea in 2, vomiting in 1, anorexia and asthenia in 2, and dehydration in 1. Severe hematologic toxicities (grade 3-4) were seen more frequently with 10 patients experiencing grade 3-4 neutropenia, 2 with grade 4 thrombocytopenia and 2 with grade 3 anemia. Neutropenia requiring hospitalization occurred in 3 patients. Dose-limiting neutropenia was observed at 220 mg/m2/day. The maximum tolerated dose was determined to be 160 mg/m2/day. No tumor responses were observed in this study. Six patients experienced stable disease, including one who has stable disease after having received 34 courses of CS-682. After oral administration, CS-682 is rapidly absorbed and metabolized to CNDAC, which is further metabolized by cytidine deaminase to the inactive product CNDAU. Peak plasma concentrations of CNDAC were achieved 2.2 +/- 0.9 h after drug administration and the terminal elimination half-life was 1.7 +/- 1.5 h. Measurable concentrations of CNDAU were first seen 0.60 +/- 0.31 h, peak plasma concentrations were achieved 3.1 +/- 0.9 h after the CS-682 dose, and the terminal elimination half-life was 2.3 +/- 1.7 h. The recommended phase 2 starting dose for the 3 days/week regimen of CS-682 is 160 mg/m2/day for 4 weeks repeated after a 2-week rest period.