RESUMO
BACKGROUND: The pancreatic tumor microenvironment is rich in receptors for platelet-derived growth factor (PDGFRs). Imatinib mesylate (IM) inhibits PDGFRs and decreases tumor interstitial fluid pressure, potentially improving drug access. These data and promising results in a phase 1 trial formed the rationale for a phase 2 trial combining IM and gemcitabine (GEM) in pancreatic cancer. METHODS: Eligibility criteria included chemotherapy-naïve, locally advanced or metastatic pancreatic cancer; ECOG (Eastern Cooperative Oncology Group) performance status ≤2; and adequate end-organ function. The primary end point was progression-free survival (PFS). Secondary end points included response rate, toxicity, and overall survival (OS). GEM was given at 1200 mg/m(2)/120 min on days 3 and 10. IM (400 mg) was taken orally on days 1 to 5 and 8 to 12 of a 21-day cycle. Response was assessed every 3 cycles. RESULTS: Forty-four patients from 7 centers were enrolled from October 2005 through July 2009. Median age was 62 years. The median number of cycles completed was 3 (range, 0-17). Common adverse effects included neutropenia, nausea, anemia, and fatigue. Half the patients required dose reductions. There were no complete responses to therapy. During treatment, 1 patient showed a partial response, 16 had stable disease, and 18 had progressive disease. The median PFS was 3.9 months (95% confidence interval, 2.1-5.1), the median OS was 6.3 months (95% confidence interval, 5.2-8.5), and the 1-year survival rate was 25.6% (95% confidence interval, 13.8-39.1). CONCLUSION: IM in combination with GEM is tolerated in locally advanced, metastatic, or recurrent pancreatic cancer, but does not show a statistically significant PFS or OS benefit over chemotherapy with GEM alone.
RESUMO
We conducted a study to determine the dose-limiting toxicity of an extended dosing schedule of temozolomide (TMZ) when used with a fixed dose of BCNU, or 1,3-bis(2-chloroethyl)-1-nitrosourea (carmustine), taking advantage of TMZ's ability to deplete O6-alkylguanine-DNA-alkyltransferase and the synergistic activity of these two agents. Patients with malignant gliomas who had undergone radiation therapy were eligible. Patients were treated with TMZ for 28 days, followed by a 28-day rest (1 cycle). The TMZ was started at 50 mg/m2 and increased in 10-mg/m2 increments; a fixed dose of BCNU (150 mg/m2) was given within 72 h of starting TMZ. A standard phase 1 dose-escalation scheme was used with 3 patients per cohort. Fourteen glioblastoma patients and 10 anaplastic astrocytoma patients were treated. The dose-limiting toxicity was myelosuppression at 90 mg/m2 of TMZ. The total number of cycles given was 73 (median number was 2). Six patients (25%) required a dose reduction in BCNU, and six were removed from study for hematologic toxicity after cycle 1; three patients overlapped. The median time to progression and overall survival were, respectively, 82 and 132 weeks for anaplastic astrocytomas and 14 and 69 weeks for glioblastomas. We conclude that the combination of BCNU and the extended dosing schedule of TMZ is feasible and that the maximal tolerated dose of a 28-day course of TMZ is 80 mg/m2 when combined with a fixed dose of BCNU at 150 mg/m2. This is the recommended dose for phase 2, but myelosuppression after cycle 1 suggests that long-term treatment may be difficult.
