Subject(s)
Mouth Neoplasms/diagnosis , Mouth Neoplasms/etiology , Pain, Postoperative/prevention & control , Plasmacytoma/diagnosis , Plasmacytoma/etiology , Tooth Extraction/adverse effects , Aged , Diagnosis, Differential , Female , Humans , Mouth Mucosa/pathology , Pain, Postoperative/etiology , Treatment OutcomeSubject(s)
Antineoplastic Agents/therapeutic use , Chromosome Deletion , Chromosomes, Human, Pair 5 , Myelodysplastic Syndromes/genetics , Thalidomide/analogs & derivatives , Aged , Blood Transfusion , Female , Humans , Lenalidomide , Male , Myelodysplastic Syndromes/drug therapy , Thalidomide/therapeutic useABSTRACT
BACKGROUND: The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) reverses the O6-methylguanine (O6-meG) lesion induced by dacarbazine. Depletion of MGMT can be achieved using O6-meG pseudosubstrates. Herein, we report the first phase I experience of the novel O6-meG pseudosubstrate lomeguatrib, combined with dacarbazine. METHODS: This is a phase I dose-escalation study to determine the maximum tolerated dose and recommended phase II dose (RP2D) of lomeguatrib combined with a single dose of dacarbazine on a 21-day schedule. RESULTS: The vast majority of the 41 patients enrolled had metastatic melanoma (36/41) and most had no previous chemotherapy (30/41). The most frequent non-hematological adverse events (AEs) were nausea (52%), and fatigue (42%). The most frequent AEs of grade 3-4 severity were neutropaenia (42%), leukopaenia (17%), and thrombocytopaenia (12%). Only 1 patient had a partial response and 10 patients had stable disease. CONCLUSION: The RP2D of lomeguatrib was 40 mg orally twice daily for 10 days combined with 400 mg m(-2) of dacarbazine IV on day 2. Oral administration of lomeguatrib substantially increases the haematological toxicity of dacarbazine consistent with experience with other O6-meG pseudosubstrates.
