Randomized trial of the combination of lomeguatrib and temozolomide compared with temozolomide alone in chemotherapy naive patients with metastatic cutaneous melanoma.
نویسندگان
چکیده
PURPOSE To evaluate tumor response, pharmacodynamic effects, and safety of a combination of lomeguatrib (LM), an O6-methylguanine DNA-methyltransferase (MGMT) inactivator, and temozolomide (TMZ), TMZ alone, and LM/TMZ after disease progression on TMZ alone in patients with advanced melanoma. PATIENTS AND METHODS Patients with unresectable stage III or IV cutaneous melanoma who had no prior systemic chemotherapy were randomly assigned to receive either 40 to 80 mg LM and 125 mg/m2 TMZ or 200 mg/m2 TMZ on days 1 through 5 of each 28-day treatment cycle. Drugs were administered orally for up to six cycles of treatment. Patients on TMZ alone were offered LM/TMZ at progression, if fit enough to receive treatment. RESULTS One hundred four patients were enrolled, with 52 in each trial arm. Twenty-seven TMZ-treated patients received LM/TMZ after progression on TMZ. Unexpectedly, analysis of tumor biopsies showed rapid recovery of MGMT after LM/TMZ with 40 mg/d LM. Therefore, doses of LM were escalated to 60 then 80 mg/d. Tumor response rates were 13.5% with LM/TMZ and 17.3% with TMZ alone. No patient responded to LM/TMZ having progressed through TMZ. Median time to disease progression was 65.5 days for LM/TMZ and 68 days for TMZ. All treatments were well tolerated, although hematologic and gastrointestinal adverse events were common. A higher incidence of hematological adverse events was observed in the LM/TMZ combination arm. CONCLUSION The efficacy of LM and TMZ in the current dosing schedule is similar to that of TMZ alone. To maintain MGMT depletion in tumor dosing of LM needs to be continued beyond that of TMZ.
منابع مشابه
Phase II randomized trial comparing high-dose IFN-α2b with temozolomide plus cisplatin as systemic adjuvant therapy for resected mucosal melanoma.
PURPOSE Mucosal melanoma is rare and associated with extremely poor prognosis. However, standard adjuvant therapy for mucosal melanoma has not been established. We conducted a randomized phase II clinical trial in patients with resected mucosal melanoma to compare the efficacy and safety of high-dose IFN-α2b (HDI) and temozolomide-based chemotherapy as adjuvant therapy. EXPERIMENTAL DESIGN Pa...
متن کاملTemozolomide for the treatment of metastatic melanoma
QUESTIONS What is the role of single-agent temozolomide in the treatment of patients with metastatic melanoma? In comparison with single-agent temozolomide, does the addition of interferon-alpha to temozolomide improve disease-free survival, overall survival, or response rates? In comparison with single-agent temozolomide, does the addition of thalidomide to temozolomide improve disease-free su...
متن کاملTemozolomide for Treating Malignant Melanoma.
Melanoma is one of the most malignant forms of skin cancer; with a rapidly increasing prevalence. Early-stage melanoma is curable, but advanced metastatic melanoma is almost always fatal, and patients with such advanced disease have short median survival. Surgery and radiotherapy play a limited role in the treatment of metastatic melanoma. Rather, chemotherapy remains the mainstay of treatment,...
متن کاملIn Vitro Radiosensitizing Effects of Temozolomide on U87MG Cell Lines of Human Glioblastoma Multiforme
Background: Glioma is the most common primary brain tumor with poor prognosis. Temozolomide (TMZ) has been used with irradiation (IR) to treat gliomas. The aim of the present study was to evaluate the cytotoxic and radiosensitizing effect of TMZ when combined with high-dose and high-dose rate of gamma irradiation in vitro.Methods: Two ‘U87MG’ cell lines and skin fibroblast were cultured and ass...
متن کاملPhase I study of the poly(ADP-ribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors.
PURPOSE One mechanism of tumor resistance to cytotoxic therapy is repair of damaged DNA. Poly(ADP-ribose) polymerase (PARP)-1 is a nuclear enzyme involved in base excision repair, one of the five major repair pathways. PARP inhibitors are emerging as a new class of agents that can potentiate chemotherapy and radiotherapy. The article reports safety, efficacy, pharmacokinetic, and pharmacodynami...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Journal of clinical oncology : official journal of the American Society of Clinical Oncology
دوره 25 18 شماره
صفحات -
تاریخ انتشار 2007