ArticlesTwo dosing regimens of tosedostat in elderly patients with relapsed or refractory acute myeloid leukaemia (OPAL): a randomised open-label phase 2 study
Introduction
Treatment outcomes for elderly patients with acute myeloid leukaemia (AML) have not improved substantially since the development of cytarabine and anthracycline-based regimens several decades ago.1, 2, 3 This situation might be due to the low tolerability in this population for the adverse effects of such treatments, as well as a high prevalence of cytogenetic predictors of poor outcome. The problem is even greater in patients who are refractory to, or have relapsed after, first-line treatment. The only drug ever approved for this indication, gemtuzumab ozogamicin, was recently withdrawn from the market.
Tosedostat is a novel oral agent that targets aminopeptidases, which have a key role in the protein cell cycle (appendix). Aminopeptidase inhibition results in the aminoacid deprivation response, which occurs selectively in transformed cells and leads to upregulation of proapoptotic factors including CHOP and NOXA,4 activation of stress-related pathways such as NFκB, and inhibition of mTOR, which switches off protein synthesis. Tosedostat induces the aminoacid deprivation response in several cell lines in vitro, including solid tumour, leukaemia, and myeloma cell lines, and has shown antineoplastic activity in various in-vivo solid tumour models.5 Tosedostat is administered as an oral ester moiety with an esterase sensitive motif. Inside the cell the ester is hydrolysed to a polar acid moiety, which is poorly membrane permeable and therefore trapped in the cell. Tosedostat has shown synergy in vitro with a wide range of other drugs used to treat solid and haematological cancers including chemotherapy agents, hypomethylating agents, and others.5
Tosedostat has been given to patients in phase 1–2 studies in both solid tumours and haematological malignancies. In a phase 1–2 study in 40 patients with solid tumours treated with tosedostat as a single drug,6 a maximum acceptable dose of 240 mg once daily was established, with one patient achieving a durable partial response and seven having confirmed stable disease. The most common adverse events at any grade were fatigue, diarrhoea, and peripheral oedema. In a phase 1–2 study in 57 patients with haematological malignancies,7 a maximum acceptable dose of 130 mg once daily was noted and seven bone marrow complete responses and seven partial responses occurred in a subset of 51 patients with AML, of which six bone marrow complete responses and five partial responses occurred in the 35 patients who were refractory or relapsed to previous treatment. The most common adverse events at any grade were thrombocytopenia, fatigue, and peripheral oedema. The maximum acceptable dose for haematological malignancies was lower than that for solid tumours, and was mainly due to several cases of thrombocytopenia, a common event in the patient population enrolled. We decided that further evaluation of the optimum doses used in haematological malignancies was appropriate. We designed the OPAL study (CHR-2797-038) to further evaluate the safety and efficacy of two dosing regimens of tosedostat in patients with relapsed or refractory AML.
Section snippets
Patients
OPAL was a phase 2 randomised study undertaken in 20 centres in the USA (16), Canada (two), and the Netherlands (two). Patients were eligible if they were aged 60 years or older with AML per WHO classification (excluding acute promyelocytic leukaemia) that required first salvage treatment after primary induction for AML that resulted in no complete remission or a complete remission that lasted less than 12 months, with an Eastern Cooperative Oncology Group performance score of 2 or less,
Results
76 patients were randomly assigned to treatment groups, of whom 73 received at least one dose of tosedostat (figure 2). The first patient was assigned to a group on Oct 21, 2009, and the last on Sept 16, 2010. The last study visit was on March 21, 2011. Patients received a mean 69·3 days (SD 52·5; median 54 [range 3–177]) of tosedostat overall, with little difference between cohorts (table 1). 22 (30%) patients completed more than 84 days (3 months) of tosedostat, but 18 (25%) patients
Discussion
In the OPAL study, seven (10%) of 73 patients treated with tosedostat achieved complete remission or a complete remission with incomplete platelet recovery: two (5%) in the 120 mg group and five (14%) in the 240 mg to 120 mg group. The most common adverse events at grade 3 or worse were febrile neutropenia, thrombocytopenia, fatigue, dyspnoea, and pneumonia. No clear differences were noted in efficacy or safety between the two dose schedules, but a promising 16 (22%) patients achieved an
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2020, Blood AdvancesCitation Excerpt :Inhibition of aminopeptidases by tosedostat and its metabolite leads to intracellular accumulation of small peptides, which in transformed cells of the hematopoietic lineage appears to cause a deficiency of free amino acids for new protein synthesis.15 When used as a single agent, tosedostat induced an overall response rate of 27% in elderly patients with AML.16,17 Cytarabine has been widely used in the treatment of AML for several decades, and the safety profile is well characterized.
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2016, Blood ReviewsCitation Excerpt :In the 51 AML patients, there were 3 CRs, 1 CRp, and 3 MLFS [83]. In the OPAL phase 2 study, patients > 60 years with relapsed/refractory AML were assigned to 2 different tosedostat dosing regimens [84]. In the 73 patients, there was one CR and 6 CRis.
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2015, Leukemia ResearchCitation Excerpt :There are 2 ongoing phase 2 trials evaluating decitabine combinations in this setting. Tosedostat is an orally bioavailable aminopeptidase inhibitor with single-agent activity in older patients with relapsed and refractory AML [57]. A phase 2 trial evaluating tosedostat plus decitabine vs tosedostat plus cytarabine (NCT01567059) was suspended due to a partial clinical hold being placed on tosedostat by the FDA in June 2013 [58].