Background: Tosedostat is an oral aminopeptidase inhibitor that has anti-neoplastic activity in a variety of malignancies. Pre-clinical assays have demonstrated synergy between tosedostat and both cytarabine and hypomethylating agents. We performed a randomized, open-label Phase II trial to determine the rates of complete remission (CR) and 4 month overall survival using tosedostat in combination with intermediate-dose cytarabine or decitabine in patients with untreated AML or high-risk MDS.

Methods: Patients ≥60 years old were randomized in a 1:1 fashion to receive tosedostat 120 mg daily by mouth days 1-21 with either 5 days of intravenous cytarabine 1 g/m2/day or decitabine 20 mg/m2/day delivered every 35 days for up to three cycles. Eight patients received 180 mg tosedostat daily continuously. Patients who obtained a CR or CR with incomplete blood count recovery (CRi) after 3 cycles of therapy were eligible to receive up to 2 additional cycles (maximum of 5).

Results: Thirty-four patients with a median age of 70 (range, 60-83) years were treated, with 17 each receiving either tosedostat/cytarabine or tosedostat/decitabine. Twenty-nine patients (85%) had AML and 5 (15%) had MDS RAEB-2. Nineteen patients (56%) had cytogenetics with intermediate-risk, 14 (41%) adverse-risk, and 1 (3%) favorable-risk by European Leukemia Net criteria. Seven patients had FLT3/ITD mutations with normal cytogenetics. Fifteen patients (44%) had secondary AML/MDS or antecedent hematologic disorder. The median duration of treatment was 3 months. The overall CR/CRi rate was 53% (9 in each arm), with 14 patients (41%) achieving a CR and 4 patients (12%) a CRi. CR/CRi was attained in 6 patients with adverse cytogenetics and 4 additional patients with FLT3 mutations. Fourteen patients (41%) were taken off study after a median of 2 cycles due to lack of response or disease progression. With a median follow-up of 11.2 months (range, 0.5-22.3 months), the median overall survival was 11.5 months (95% CI, 5.2-16.7). Twenty-three patients (67.6%) were treated as outpatients and 10 of these patients (44%) required hospitalization during treatment for febrile neutropenia. There were no Grade 3-4 non-hematologic toxicities requiring withdrawal from the study.

Conclusions: Tosedostat in combination with cytarabine or decitabine likely provides a CR/CRi rate of >50% with acceptable toxicity in older patients with untreated AML/ MDS. This approach delivered predominantly as outpatient therapy suggests that further study in a larger, controlled trial may be warranted.


Off Label Use: Pravastatin is not FDA approved for treatment of AML. Wang:CTI Biopharma: Employment. Singer:CTI BioPharma, Corp: Employment, Equity Ownership.

Author notes


Asterisk with author names denotes non-ASH members.