Oral clofarabine for relapsed/refractory non-Hodgkin lymphomas: results of a phase 1 study

Abstract

We conducted a phase 1 trial evaluating the oral nucleoside analogue clofarabine in patients with relapsed/refractory non-Hodgkin lymphoma. Patients were treated once daily on days 1 through 21 of a 28 day cycle for a maximum of 6 cycles. The study was conducted with a 3+3 design with ten additional patients treated at the recommended phase 2 dose. Thirty patients were enrolled including indolent B-cell lymphomas (21), mantle cell (6), and diffuse large B-cell lymphoma (3). The primary toxicities were hematologic including grade 3–4 neutropenia (53%) and thrombocytopenia (27%). Three mg was determined to be the recommended phase 2 dose. Tumor volume was reduced in 70% of patients, and the overall response rate was 47% including 27% complete remissions. Responses were seen in indolent B-cell lymphomas and mantle cell lymphoma. At a median follow-up of 17 months, 68% of responding patients remain in ongoing remission. Oral clofarabine was well tolerated with encouraging efficacy in indolent B-cell lymphomas and mantle cell lymphomas, warranting further investigation.

Phase I study of oral clofarabine consolidation in adults aged 60 and older with acute myeloid leukemia

“…While hematologic toxicity was frequent in the oral clofarabine regimen reported here, there were no episodes of febrile neutropenia and a low incidence of infection observed. Our toxicity data are similar to those reported recently in a phase I trial of oral clofarabine for relapsed/refractory non- Hodgkin lymphoma, with frequent grade 3-4 neutropenia (53%) and thrombocytopenia (27%), but low rates of neutropenic fever (3%), grade 3-4 infection (10%), and other ≥ grade 3 adverse events (27). Furthermore, oral clofarabine was associated with encouraging activity, as the median relapse-free survival was 28.35 months and the median overall survival was not attained with a median follow-up time of 13.3 months, at doses of clofarabine of 2 mg daily or higher.…”

“…Furthermore, in preclinical mouse models, prolonged oral administration of clofarabine demonstrated increased anti-tumor effect compared to shorter duration IV administration. A recent report demonstrated tolerability and encouraging efficacy of oral clofarabine for the treatment of relapsed/refractory non-Hodgkin lymphoma (27). …”

Optimal Stopping for Interval Estimation in Bernoulli Trials

“…Remark 1. We must emphasize that the constraint in (2) does not guarantee that the desired coverage probability will also hold for each individual θ, namely P(|θ T − θ| > h|θ) ≤ α, a property which is particularly desirable in practice. Perhaps, a more meaningful problem to consider in place of (2) would have been…”

“…Interval estimation of a binomial proportion θ is one of the most basic problems in statistics with many important real-world applications. Some classical applications include interval estimation of the prevalence of a rare disease [1]; interval estimation of the overall response rate in clinical trials [2]; and accuracy assessment in remote sensing [3]. In these applications, the sample size is fixed in advance, and a confidence interval for θ is obtained.…”

Sequential therapy combining clofarabine and T-cell-replete HLA-haploidentical haematopoietic SCT is feasible and shows efficacy in the treatment of refractory or relapsed aggressive lymphoma

“…An additive a GVL effect mediated by HLA disparity is presumed. 7,8 Clofarabine has shown significant anti-tumour activity as a single agent in the treatment of NHL, including rituximabrefractory patients, 9,10 and was feasible and effective in HLA-matched and mismatched allo-HSCT. [11][12][13][14] Furthermore, T-cell-replete HLA-haploidentical transplantation using high-dose CY for post-grafting immunosuppression is reported to be associated with low rates of non-relapse mortality (NRM), and favourable results in the treatment of lymphoma have been observed.…”