ABSTRACT
Lonafarnib is an orally bio-available farnesyltransferase inhibitor that prevents farnesylation of specific target proteins including Ras. In a multicenter study, 67 patients with advanced myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) were treated with a continuous oral dose of 200-300 mg of lonafarnib and were evaluated for hematologic, pathologic and pharmacodynamic response. The median age of patients was 70 years (range 44-86). There were 32 patients with MDS (RAEB-20 and RAEB-t-12) and 35 with CMML. Overall 16 (24%) of the patients responded with two patients achieving a complete remission and one a partial response. Responses were seen in 6/32 and 10/35 patients with MDS and CMML, respectively. Of the 19 patients who were platelet transfusion-dependent prior to treatment, 5 (26%) became transfusion-free for a median duration of 185 days. A decrease in the farnesylation of the HDJ-2 protein measured in patient-derived cells was observed in the majority of patients during treatment with lonafarnib, but no clear correlation between changes in farnesylation and clinical effect could be made. Gastrointestinal toxicity was significant with 19% of patients discontinuing therapy due to diarrhea, nausea and/or anorexia. Lonafarnib has demonstrable activity in patients with advanced MDS and CMML.
Subject(s)
Leukemia, Myelomonocytic, Chronic/drug therapy , Myelodysplastic Syndromes/drug therapy , Piperidines/administration & dosage , Pyridines/administration & dosage , Adult , Aged , Aged, 80 and over , Drug Monitoring , Enzyme Inhibitors/therapeutic use , Farnesyltranstransferase/antagonists & inhibitors , Farnesyltranstransferase/metabolism , Gastrointestinal Diseases/chemically induced , Humans , Leukemia, Myelomonocytic, Chronic/complications , Maximum Tolerated Dose , Middle Aged , Myelodysplastic Syndromes/complications , Piperidines/toxicity , Pyridines/toxicity , Remission Induction , Treatment OutcomeABSTRACT
Long-term survival in epithelial ovarian cancer remains problematic despite multimodality therapy. A fundamental difficulty is the development of tumor resistance to platinum compounds. Analogs have been developed that demonstrate activity in platinum-resistant cell lines both in vitro and in vivo. Lobaplatin (D-19466), a third-generation compound, demonstrates significant activity in carboplatin and cisplatin-resistant cell lines. Lobaplatin was given to 17 assessable patients with platinum-refractory ovarian cancer. The drug was initially administered at a dose of 50 mg/m2 but was later reduced to 40 mg/m2 because of excessive thrombocytopenia. Nine patients required red cell transfusions during therapy. Cycles were repeated every 21-35 days (median cycle length 28 days). No objective responses were observed. Lobaplatin has no activity in platinum-resistant epithelial ovarian cancer.
