A Phase I/II Study Of Cytarabine Or Azacitidine In Combination With Tosedostat In Older Patients With AML Or High-Risk MDS

The aminopeptidase inhibitor tosedostat is an orally bioavailable novel chemotherapeutic, functioning through enzymatic blockade of intracellular protein degradation and re-synthesis. Encouraging results have been observed with tosedostat monotherapy in Phase I and II trials of relapsed and refractory elderly AML patients.

This Phase I/II trial explores the safety, tolerability and activity of tosedostat in combination with cytarabine or azacitidine in older patients with AML or high-risk MDS.

Eligibility includes age >60 years, performance status of 0-2, with relapsed/refractory AML or high-risk MDS having failed prior hypomethylating agent (HMA) and/or lenalidomide therapy. All subjects received tosedostat 120mg orally once daily for 28 day cycles, with either subcutaneous (SQ) cytarabine at starting dose of 7.5mg twice daily for 10 days, or azacitidine (AZA) IV/SQ at starting dose of 50mg/m² daily for 7 days, per investigator’s choice. A modified 3+3 dose escalation design was used in the Phase I portion to identify the maximum tolerated dose independently for both arms. Escalation to the predefined target dose levels of 10mg SQ cytarabine twice daily for 10 days, or azacitidine 75mg/m² IV/SQ daily for 7 days per 28 day cycle was achieved. Dose escalation to 180mg daily tosedostat was allowable for patients not achieving a CR after 4 weeks on therapy.

From November 2012 to April 2013, the Phase I portion completed enrollment with a total of 18 patients (10 with AZA, 8 cytarabine). Six patients discontinued prior to completion of cycle 1 for reasons other than study-drug related toxicity or progressive disease and were replaced; they are considered as non-responders in the primary efficacy analysis. Median age was 73 (range 60-81), and 56% were male. 13 patients (72%) had secondary or therapy-related AML, of which 11 (61%) had prior MDS. The median number of prior treatments for MDS and/or AML was 2 (range 1-6), and 11 (61%) had received prior HMA therapy. Median white blood cell (WBC) count at study start was 5x10⁹/L (range 0.3 – 44.2), with median peripheral blood blasts of 27% (range 0-95%), and bone marrow blasts 57% (range 6-90%). The majority (61%) of patients had complex cytogenetics or abnormal cytogenetics involving chromosome 5 and/or 7; six patients (33%) had diploid cytogenetics. Molecular analysis identified 1 FLT3-ITD, 3 DNMT3A, 2 JAK2 V617F, 2 NRAS, 2 KRAS, and 1 IDH1 mutation.

Median duration on study was 49 days (range 13 – 254), with median overall survival (OS) of 3.1 months (range 0.4-8.5) and an overall response rate (ORR) of 33% (CR/CRp/MLFS 17%, PR 17%). ORR was 50% (CR/CRp/MLFS 25%, PR 25%) in fully evaluable patients remaining on study for >28 days. Median OS for patients with CR/CRp/MLFS and PR was 7.3 and 3.5 months, respectively, while OS for unevaluable patients or those with progressive disease was 29 days. On univariate analysis, the presence of a diploid karyotype (p=0.001) or WBC count <4x10⁹/L (p=0.036) associated with an improved ORR.

The most common non-hematologic toxicities regardless of attribution (all %; grade >3) included pleural and pericardial effusions (72%; 0%), dyspnea (67%; 0%), peripheral edema (61%; 6%), pneumonia (56%; 50%), fatigue (50%; 0%), diarrhea (50%; 0%), and cough (39%; 0%). Additional cardiac toxicities included systolic dysfunction (17%; 6%), QTc prolongation (50%; 6%) and myocardial infarction (MI) (11%; 11%). One fatal acute coronary event on cycle 2, day 2 of tosedostat 180mg and AZA 75mg/m² was considered possibly related to study drug.

The combination of tosedostat with low-dose cytarabine or azacitidine appears effective in a population with an overall very poor prognosis. Additional safety and efficacy evaluations are ongoing. Updated results and follow-up will be presented at the annual meeting.

No relevant conflicts of interest to declare.