A phase I/II study of exisulind in combination with docetaxel/carboplatin in patients with metastatic non-small-cell lung cancer.

Exisulind is a sulfone derivative of sulindac that induces apoptosis and demonstrates synergy with docetaxel in lung cancer models. This study evaluated the safety, efficacy, and pharmacokinetic interactions of exisulind and docetaxel/carboplatin in patients with metastatic non-small-cell lung cancer (NSCLC). Fifty-seven patients received 218 cycles of docetaxel (75 mg/m2) and carboplatin (area under the curve, 5.0) in combination with exisulind (125-250 mg orally twice daily). Two complete responses and 9 partial responses were observed among the 47 patients assessable for response (overall response rate, 23%). The median duration of response was 5.9 months and median survival was 9.4 months. The 1- and 2-year survival rates are 35% and 14%, respectively. The hematologic toxicities were consistent with those previously reported with docetaxel/carboplatin. The most common nonhematologic toxicities were mild to moderate fatigue, anorexia, nausea, and vomiting. The addition of exisulind to the chemotherapy regimen did not interfere with the metabolism or elimination of docetaxel and vice versa, and docetaxel did not interfere with the pharmacokinetic parameters of exisulind. This trial did not allow direct comparison of patients receiving docetaxel/carboplatin with and without exisulind, but when compared with historical data of docetaxel/carboplatin alone, the addition of exisulind does not appear to enhance antitumor activity, duration of response, or survival. Although preclinical data demonstrate increased apoptosis and prolonged survival for the combination of exisulind and docetaxel, multiple clinical trials do not support further clinical development of this combination regimen in patients with advanced NSCLC.

Rituximab with or without bevacizumab for the treatment of patients with relapsed follicular lymphoma.

INTRODUCTION/BACKGROUND: Inhibition of tumor angiogenesis by the interruption of VEGF pathway signaling is of therapeutic value in several solid tumors. Preclinical evidence supports similar importance of the pathway in non-Hodgkin lymphoma. In this randomized phase II trial, we compared the efficacy and toxicity of rituximab with bevacizumab versus single-agent rituximab, in patients with previously-treated follicular lymphoma. PATIENTS AND METHODS: Patients (n = 60) were randomized (1:1) to receive rituximab (375 mg/m(2) intravenously [I.V.] weekly for 4 weeks) either as a single agent or with bevacizumab (10 mg/kg I.V. on days 3 and 15). Patients with an objective response or stable disease at week 12 received 4 additional doses of rituximab (at months 3, 5, 7, and 9); patients who received rituximab/bevacizumab also received bevacizumab 10 mg/kg I.V. every 2 weeks for 16 doses. RESULTS: After a median follow-up of 34 months, PFS was improved in patients who received rituximab/bevacizumab compared with patients who received rituximab alone (median 20.7 vs. 10.4 months respectively; HR, 0.40 (95% confidence interval [CI], 0.20-0.80); P = .007). Overall survival was also improved numerically (73% vs. 53% at 4 years), but did not reach statistical significance (HR, 0.40 (95% CI, 0.15-1.05); P = .055). The addition of bevacizumab increased the toxicity of therapy, but both regimens were well tolerated (no grade 4 toxicity). CONCLUSION: The addition of bevacizumab to rituximab significantly improved PFS. The role of angiogenesis inhibition in the treatment of follicular lymphoma requires further definition in larger clinical trials.

Combination chemotherapy with gemcitabine and irinotecan in patients with previously treated carcinoma of an unknown primary site: a Minnie Pearl Cancer Research Network Phase II trial.

BACKGROUND: The current study was performed to evaluate the activity of combination chemotherapy with gemcitabine and irinotecan in patients with previously treated carcinoma of an unknown primary site. METHODS: Patients with carcinoma of an unknown primary site who had received one previous chemotherapy regimen were eligible for this study. All patients received gemcitabine at a dose of 1000 mg/m2 intravenously (i.v.) and irinotecan at a dose of 100 mg/m2 i.v. on Days 1 and 8; treatment courses were repeated every 21 days. Patients were evaluated for response after completing two courses of treatment; responders/stable patients continued treatment for a recommended six courses. RESULTS: Forty patients entered this multicenter, community-based Phase II trial between September 2000 and July 2003. Four of these 40 patients (10%) achieved objective responses (a partial response in 3 patients and a complete response in 1 patient). An additional 17 patients (43%) had stable disease/minor response at first reevaluation; 7 of these patients (18%) remained stable for longer than 6 months. The median survival for the entire group was 4.5 months, with 1-year and 2-year survival rates of 25% and 13%, respectively. The treatment was well tolerated by most patients. Neutropenia was the most common Grade 3/4 toxicity (according to the National Cancer Institute Common Toxicity Criteria, version 3.0) (occurring in 36% of patients). Myelosuppression-related complications were uncommon, as were severe nonhematologic toxicities. CONCLUSIONS: The combination of gemcitabine and irinotecan has modest activity and is well tolerated in patients with recurrent/refractory carcinoma of an unknown primary site. Treatment-related toxicity, particularly myelosuppression, appears to be less severe than toxicity produced by the taxane and platinum regimens frequently used in the first-line therapy of these patients. Evaluation of the gemcitabine and irinotecan combination as first-line therapy is indicated.

A Phase I trial of protracted oral fixed-dose temozolomide.

BACKGROUND: The current Phase I trial was conducted to determine the dose-limiting toxicity (DLT), maximum tolerated dose, and recommended Phase II dose of oral fixed-dose temozolomide when administered for 5 of every 7 days on a continuous basis. METHODS: Patients received a fixed dose of temozolomide daily for 5 of every 7 days continuously. Four weeks of treatment were considered 1 treatment cycle. Patients were accrued at 7 different dose levels ranging from 100 mg/day to 360 mg/day. RESULTS: Forty-six patients received 111 cycles of therapy. DLT consisted of myelosuppression, particularly thrombocytopenia. The primary nonhematologic toxicities were nausea and emesis, which were easily controlled with antiemetics. CONCLUSIONS: Protracted administration of temozolomide at a fixed dose of 300 mg/day for 5 of every 7 days continuously was well tolerated and allowed greater dose intensity compared with various other schedules. This regimen could potentially increase antitumor activity as protracted temozolomide schedules inhibit DNA repair by depletion of the repair protein O6-methylguanine-DNA methyltransferase.

Weekly paclitaxel, estramustine phosphate, and oral etoposide in the treatment of hormone-refractory prostate carcinoma: results of a Minnie Pearl Cancer Research Network phase II trial.

BACKGROUND: The objective of the current study was to evaluate the efficacy and toxicity of weekly paclitaxel, oral etoposide, and estramustine phosphate in the treatment of patients with advanced, hormone-refractory prostate carcinoma. METHODS: Patients with hormone-refractory prostate carcinoma who had received no more than one previous chemotherapy regimen were eligible for this trial. Forty-two patients were treated between February 1998 and March 2000. Toxicity was excessive in the first 3 patients treated (Grade 3-4 leukopenia, 3 patients; death due to sepsis, 1 patient); the remaining 39 patients received lower doses of etoposide and estramustine phosphate (paclitaxel 50 mg/m(2) as a 1-hour, intravenous infusion on Days 1, 8, 15; etoposide 50 mg orally twice daily on Days 1-10; and estramustine phosphate 280 mg orally 3 times daily on Days 1-10). Courses were repeated every 28 days. Patients were evaluated for objective and/or serologic response after two courses of treatment; responding patients continued treatment for six courses. RESULTS: Fourteen of 40 evaluable patients (35%) had either an objective response or a serologic response to treatment. The median survival for the entire group was 9.5 months, with 1-year, 2-year, and 3-year survival rates of 38%, 12%, and 10%, respectively. Neutropenia was the most common Grade 3-4 toxicity and occurred in 38% of patients (11% of courses). Thirteen patients (33%) had severe fatigue, and 2 patients had treatment-related deaths due to sepsis. CONCLUSIONS: Although the three-drug combination had activity in patients with hormone-refractory prostate carcinoma, the results did not appear any better than the results achieved with less toxic taxane/estramustine phosphate combinations. Further development of this three-drug regimen is not recommended.