A phase II study of gefitinib, 5-fluorouracil, leucovorin, and oxaliplatin in previously untreated patients with metastatic colorectal cancer.

PURPOSE: We investigated the gefitinib, 5-fluorouracil (5-FU), leucovorin and oxaliplatin (IFOX) regimen as first-line therapy in patients with metastatic colorectal cancer. EXPERIMENTAL DESIGN: Eligible patients had stage IV colorectal adenocarcinoma, and had not received prior chemotherapy for metastatic disease. Each cycle consisted of 14 days. Cycle 1 consisted of oxaliplatin, leucovorin, and 5-FU (FOLFOX-4). All subsequent cycles consisted of FOLFOX-4 with gefitinib at 500 mg orally daily throughout the 14-day cycle. RESULTS: Forty-five patients were enrolled and were assessable for toxicity. Forty-three patients were assessable for response. Thirty-one of the 43 patients (72%) had either a complete or partial response by the Response Evaluation Criteria in Solid Tumors. Median overall survival was 20.5 months. Median time to progression was 9.3 months. Commonly encountered grade 3 or 4 toxicities included diarrhea in 67% of patients and neutropenia in 60%. Grade 2 acneiform skin rash typical of gefitinib occurred in 60% of patients. CONCLUSIONS: IFOX is an active first-line regimen in patients with metastatic colorectal adenocarcinoma, showing higher response rates but also increased toxicities compared with FOLFOX-4 alone in a similar patient population.

Phase I study of gefitinib, oxaliplatin, 5-fluorouracil, and leucovorin (IFOX) in patients with advanced solid malignancies.

PURPOSE: Aphase 1 study of gefitinib in combination with oxaliplatin, 5-fluorouracil and leucovorin (IFOX)was conducted to evaluate the safety and feasibility of this regimen. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of gefitinib (250 mg or 500 mg once daily) in combination with FOLFOX (oxaliplatin, 5-fluorouracil, and leucovorin). The initial dose of oxaliplatin was 70 mg/m2 with sequential dose escalation to 85 mg/m2. RESULTS: Sixteen patients received a total of 138 14-day courses of daily gefitinib in combination with FOLFOX. Escalation of gefitinib from 250 mg/d to 500 mg/d with FOLFOX was well-tolerated. In addition, no severe toxicities precluded subsequent dose escalation of oxaliplatin from 70 mg/m2 to 85 mg/m2 at which no dose-limiting toxicity was seen. No further dose escalation was performed as this represented the oxaliplatin dose administered in the standard FOLFOX-4 regimen. The most predominant toxicity was diarrhea, which was well controlled with oral antidiarrheal agents. Four partial remissions occurred in patients with metastatic colorectal cancer. CONCLUSIONS: Gefitinib as a 500 mg daily continuous dose was well tolerated in combination with full doses of FOLFOX-4.

A phase I trial of aprinocarsen (ISIS 3521/LY900003), an antisense inhibitor of protein kinase C-alpha administered as a 24-hour weekly infusion schedule in patients with advanced cancer.

PURPOSE: A phase I study was performed to determine the maximum tolerated dose (MTD), safety profile and pharmacology of aprinocarsen (ISIS 3521), an antisense oligonucleotide to protein kinase C-alpha, in patients with refractory solid tumors. EXPERIMENTAL DESIGN: Fourteen patients were treated in sequential cohorts of aprinocarsen by 24-hour continuous infusion (CIV), weekly, at doses of 6, 12, 18 and 24 mg/kg. RESULTS: One grade 4 toxicity was observed, transient grade 4 neutropenia at 18 mg/kg. Grade 3 toxicities included neutropenia at 12 mg/kg, fever and hemorrhage at 18 mg/kg, and neutropenia, nausea, and chills at 24 mg/kg. Grade 2 toxicities included thrombocytopenia myalgias, chills, headache, fatigue, fever and nausea/vomiting. Mean prothrombin times and activated partial thromboplastin times (aPTT) increased by 10% and 29% from baseline (p = 0.006 and 0.005). Mean complement split products (Bb and C3a) increased 1.6-fold and 3.6-fold (from p = 0.014 and 0.004, respectively). These changes correlated with dose and were transient with recovery to baseline by day 7. Steady state plasma concentrations (Css) of aprinocarsen were achieved within four hours. Css better described changes in aPTT than dose. Clinical evidence of complement activation was not observed. CONCLUSIONS: In contrast to 21-day protracted infusion schedules, delivery of aprinocarsen over a 24-hour infusion schedule showed concentration-dependent effects on coagulation and complement, which are consistent with nonclinical toxicology studies performed in the phosphorothioate DNA antisense drug class. These coagulation and complement changes resulted in a maximum tolerated dose 24 mg/kg.

Phase II study of gefitinib, fluorouracil, leucovorin, and oxaliplatin therapy in previously treated patients with metastatic colorectal cancer.

PURPOSE: To investigate the gefitinib, fluorouracil (FU), leucovorin, and oxaliplatin regimen (IFOX) in previously treated patients with metastatic colorectal cancer. PATIENTS AND METHODS: Eligible patients had stage IV colorectal adenocarcinoma and had demonstrated progression or intolerance to a prior chemotherapy regimen not including oxaliplatin. Each cycle consisted of 14 days. Cycle 1 consisted of oxaliplatin 85 mg/m2 intravenously (IV) during 2 hours on day 1, hours 0 to 2; leucovorin 200 mg/m2 IV on days 1 and 2, hours 0 to 2; FU 400 mg/m2 IV push on days 1 and 2; and FU 600 mg/m2 IV on days 1 and 2, hours 2 to 24 (FOLFOX-4). All subsequent cycles consisted of FOLFOX-4 with gefitinib at 500 mg/d administered orally throughout the 14-day cycle. RESULTS: Twenty-seven patients were enrolled onto the study. The median number of prior chemotherapy regimens was two, and 74% of all patients received prior irinotecan. Nine of the 27 patients (33%) and six of the 20 patients (30%) who had prior FU and irinotecan had a partial response by Response Evaluation Criteria in Solid Tumors Group criteria. Median overall survival was 12.0 months. Median event-free survival was 5.4 months. Grade 3 to 4 toxicities included neutropenia (48%), diarrhea (48%), nausea (22%), and vomiting (15%). CONCLUSION: IFOX is an active regimen in patients with previously treated metastatic colorectal adenocarcinoma, demonstrating higher response rates than those reported with FOLFOX-4 alone in a similar patient population.

A Phase II trial of aprinocarsen, an antisense oligonucleotide inhibitor of protein kinase C alpha, administered as a 21-day infusion to patients with advanced ovarian carcinoma.

BACKGROUND: It has been postulated that protein kinase C alpha (PKC-alpha) plays a pivotal role in signal transduction in tumor cancer cells. Aprinocarsen, a 20-base antisense oligonucleotide, has shown ability to inhibit PKC-alpha protein expression and inhibit tumor growth in human xenograft models. In a previous Phase I trial, the authors demonstrated the safety and some evidence of activity in ovarian carcinoma of aprinocarsen administered as a 21-day, continuous, intravenous infusion. METHODS: In this Phase II trial, 36 patients with advanced ovarian carcinoma were treated with aprinocarsen at a dose of 2 mg/kg per day delivered as a 21-day, continuous, intravenous infusion. The primary objective was to determine the antitumor response, and the secondary objectives were to evaluate toxicity and to evaluate effects on quality of life (QOL). RESULTS: Between September 1997 and December 1999, 36 patients (median age, 58 years) were enrolled in this trial. Patients were stratified into 2 groups: a platinum-sensitive group (n = 12 patients) and a platinum-resistant group (n = 24 patients). All 36 patients were evaluable for toxicity, and 27 patients were fully assessable for antitumor response after 2 cycles of therapy. All patients had received prior treatments. No objective responses were noted in the platinum-sensitive group. In the platinum-resistant group, 1 patient had some evidence of antitumor activity indicated by a decrease in serum CA 125 and stable disease on imaging studies for 8 months. No changes were noted in overall patient ratings for any of the five QOL domains. CONCLUSIONS: When it was administered as a single agent, aprinocarsen did not have significant clinical activity in patients with advanced ovarian carcinoma. Further study may be warranted in combination with platinum-based regimens.