Pemetrexed in primary central nervous system lymphoma: a phase-I dose finding study
Malesz, Alexandra Elizabeth
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OBJECTIVE: The aim of this study was to investigate the safety and tolerability of a novel anti-folate drug, pemetrexed, in the setting of a phase I clinical trial in patients with non-HIV related central nervous system lymphoma (CNSL). METHODS: In this multicenter, open-label, phase I dose finding clinical trial, pemetrexed was investigated as a single agent treatment for primary or secondary CNSL. RESULTS: A total of 18 patients were enrolled between January 2009 and November 2014. The mean age was 64.6 years old (range: 47-79). The ratio of male to female was 1:1. One out of six patients experienced a dose limiting toxicity (DLT) at dose level 1 (600mg/m2). There were no DLTs among the four patients enrolled at dose level 2 (900m/m2). Two of six patients experienced a DLT at dose level 3 (1200mg/m2). The MTD was therefore determined to be 900mg/m2. Overall, pemetrexed was well tolerated but toxicities were seen and need to be monitored. All patients experienced at least one type of toxicity of any grade. Most patients (92.9%) experienced at least one type of neurological toxicity. Grade-3 toxicities included confusion, speech impairment, and psychosis. Twelve patients (85.7%) experienced at least one bone marrow type of toxicity of any grade. These toxicities included anemia (78.6%), thrombocytopenia (57.1%), neutropenia (50%), leukocytopenia (42.9%), and lymphopenia (42.9%). Four patients experienced either grade-3 (14.3%) or grade-4 (14.3%) neutropenia. Three patients experienced grade-3 leukopenia (21.4%). One patient experienced grade-3 lymphopenia (7.1%) and two patients experienced grade-4 lymphopenia (14.3%). Twelve patients (85.7%) experienced at least one metabolic type of toxicity of any grade. A majority of these were also grade-1 or 2, with the exception of hypophosphatemia (grade-4), hyperglycemia (grade-3) and increased ALT (grade-3), increased AST (grade-3) and increased creatinine phosphokinase (CPK) (grade-4). Constitutional and gastrointestinal symptoms were seen in >60% of patients. These consisted mainly of fatigue, constipation, nausea, and anorexia. Musculoskeletal symptoms were seen in greater than 60% of patients. Less common adverse events included pain (<60%), infection (<40%), dermatologic, ocular/visual, and pulmonary/upper respiratory (<30%). The average number of cycles on treatment for all patients was 5.5 cycles. 14 patients were evaluated for response to treatment by neuroimaging (MRI) while on treatment. Of these, four patients (28.6%) showed a complete response (CR). Of those patients, 2 patients achieved this response after only 2 doses, and 2 patients after a total of 8 doses. 5 patients (35.7%) showed a partial response (PR) and four patients (28.6%) achieved stable disease (SD). The overall response rate (ORR) was determined at 92.9% (SD, PR and CR combined). CONCLUSIONS: Given this data, pemetrexed is a powerful drug and feasible alternative to existing treatment options; however, certain toxicities need to be closely monitored. Further studies are needed to assess the efficacy of pemetrexed in a larger cohort of patients with CNSL.
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