A Phase I/II study of lomustine and temozolomide in patients with cerebral metastases from malignant melanoma

Abstract

Temozolomide is an alkylating agent with activity in the treatment of melanoma metastatic to the brain. Lomustine is a nitrosurea that crosses the blood brain barrier and there is evidence to suggest that temozolomide may reverse resistance to lomustine. A multicentre phase I/II study was conducted to assess the maximum-tolerated dose (MTD), safety and efficacy of the combination of temozolomide and lomustine in melanoma metastatic to the brain. Increasing doses of temozolomide and lomustine were administered in phase I of the study to determine the MTD. Patients were treated at the MTD in phase II of the study to six cycles, disease progression or unacceptable toxicity. Twenty-six patients were enrolled in the study. In phase I of the study, the MTD was defined as temozolomide 150 mg m À2 days 1 -5 every 28 days and lomustine 60 mg m -2 on day 5 every 56 days. Dose-limiting neutropaenia and thrombocytopaenia were observed at higher doses. Twenty patients were treated at this dose in phase II of the study. No responses to therapy were observed. Median survival from starting chemotherapy was 2 months. The combination of temozolomide and lomustine in patients with brain metastases from melanoma does not demonstrate activity. The further evaluation of this combination therefore is not warranted.

Synthesis of Benzotriazine and Aryltriazene Derivatives Starting from 2‐Azidobenzonitrile Derivatives

“…[7] Furthermore, the successful antitumour drug temozolomide (3) also features the triazine ring system. [8][9][10] The first synthesis of temozolomide (3) used methyl isocyanate (MIC) as a reagent, which afforded both high purity and excellent yields. Unfortunately, due to the high toxicity of MIC and difficulties in handling it on an industrial [ and 11 as products.…”

Malignant Melanoma S3‐Guideline “Diagnosis, Therapy and Follow‐up of Melanoma”

“…Uncontrolled phase I/II or II studies examined temozolomide alone [579,581,586] or in combination with sorafenib [580], thalidomide [583], lomustine [585], cisplatin [581], and docetaxel [581]. Further trials investigated DTIC in combination with fotemustine [582], fotemustine alone [584], or thalidomide [587].…”

“…Systematic search of the literature de-novo: [480,490,501,[579][580][581][582][583][584][585][586][587] Strength of consensus: 88 %…”

Alkylating Agents

“…The schedule in those cases depends on the disease, response and concomitant therapy. The most common combination chemotherapeutic regimens are the PCV regimen (lomustine, procarbazine and vincristine) used to treat astrocytic tumours after surgery and radiation therapy, medulloblastoma and oligodendroglioma (Cairncross et al, 2006); the BOLD regimen (bleomycin, vincristine, lomustine and dacarbazine) to treat metastatic melanoma (Larkin et al, 2007), and the '8 in 1' regimen (vincristine, CCNU, procarbazine, hydroxyurea, cisplatin, Ara-C, cyclophosphamide or dacarbazine and methylprednisolone) (Gardner and Martingano, 1996).…”