Two dosing regimens of tosedostat in elderly patients with relapsed or refractory acute myeloid leukaemia (OPAL): a randomised open-label phase 2 study

doi:10.1016/S1470-2045(13)70037-8

The Lancet Oncology

Volume 14, Issue 4, April 2013, Pages 354-362

https://doi.org/10.1016/S1470-2045(13)70037-8 Get rights and content

Summary

Background

Tosedostat is a novel oral aminopeptidase inhibitor with clinical activity in a previous phase 1–2 study in elderly patients with relapsed or refractory acute myeloid leukaemia (AML). We aimed to compare two dosing regimens of tosedostat.

Methods

In this randomised phase 2 study, patients aged 60 years or older with AML that had relapsed after a first complete remission lasting less than 12 months, or had achieved no previous complete remission, were randomly assigned (1:1) to receive as first salvage tosedostat 120 mg once daily for 6 months or 240 mg once daily for 2 months followed by 120 mg for 4 months. Randomisation was by block method via an interactive web response system using a randomisation schedule generated by an external vendor, with no stratification. The study was open label. The primary endpoint was the proportion of patients who obtained a complete remission or complete remission with incomplete platelet recovery. Analyses included all patients randomly assigned to treatment groups who received at least one oral dose of tosedostat. The study is registered with ClinicalTrials.gov, number NCT00780598.

Findings

38 patients were randomly assigned to receive tosedostat 120 mg and 38 to receive the tosedostat 240 mg to 120 mg regimen. 38 patients in the 120 mg group and 35 in the 240 mg to 120 mg group received tosedostat. Seven patients (10%) had complete remission or 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 grade 3 or worse adverse events were febrile neutropenia (11 [29%] patients in the 120 mg group and ten [29%] of the 240 mg to 120 mg group), thrombocytopenia (eight [21%] and eight [23%] patients), fatigue (seven [18%] and eight [23%] patients), dyspnoea (five [13%] and seven [20%] patients), and pneumonia (four [11%] and six [17%] patients). There were five fatal adverse events deemed to be treatment-related: three in the 120 mg group and two in the 240 mg to 120 mg group. The events were acute hepatitis, respiratory failure, pneumonia, atrial fibrillation, and left ventricular dysfunction.

Interpretation

Tosedostat, at either dose schedule, has activity in older patients with relapsed or refractory AML. Additional studies of tosedostat including combination with hypomethylating agents and low-dose cytarabine in patients with high-risk myelodysplastic syndromes and AML are ongoing or planned.

Funding

Chroma Therapeutics.

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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ArticlesTwo dosing regimens of tosedostat in elderly patients with relapsed or refractory acute myeloid leukaemia (OPAL): a randomised open-label phase 2 study

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Patients

Results

Discussion

Blood

Blood

FEBS Lett

Trends in the treatment of acute myeloid leukemia in the elderly

Drugs Aging

CHR-2797: an antiproliferative aminopeptidase inhibitor that leads to amino acid deprivation in human leukaemic cells

Cancer Res

A first-in-man phase I and pharmacokinetic study on CHR-2797 (tosedostat), an inhibitor of M1 aminopeptidases, in patients with advanced solid tumors

Clin Can Res

Articles
Two dosing regimens of tosedostat in elderly patients with relapsed or refractory acute myeloid leukaemia (OPAL): a randomised open-label phase 2 study