The purpose of this study is to evaluate the efficacy and safety of tosedostat in elderly patients suffering from refractory or relapsed AML.

There is an urgent need for novel compounds and treatment strategies for elderly patients with AML, particularly those with refractory or relapsed disease for whom there are few effective treatment options. Treatment options for elderly patients are further limited by co-morbidity and tolerability constraints.

Tosedostat is a new aminopeptidase inhibitor, which in preclinical experiments has shown potent activity in both in vitro and in vivo cancer models as a single agent. In early clinical studies particularly good results have been observed in refractory and relapsed AML in older patients and these observations form the basis for the current study.

This multi-center, open label phase II study will enrol approximately 70 subjects in Part A and 130 subjects in Part B.

INCLUSION:

1. Signed, informed consent prior to any study specific procedure

2. Subjects with a confirmed diagnosis of AML according to WHO classification (excluding APL) who have had either a first CR lasting less than 12 months, or have not had a first CR and who will receive their first salvage therapy in this study [6]. For the purposes of this study, the following considerations apply:

   1. Subjects should have received only 1 induction course, but this may have consisted of more than one cycle of treatment, with different agents or doses in each cycle
   2. Induction courses should normally have consisted of agents and doses considered as standard of care for induction at the investigational site concerned
   3. Subjects may have received consolidation for any number of cycles. Consolidation will be considered as any regimens given while the subject was in remission
   4. Subjects who received hematopoietic stem cell transplant in first remission are eligible provided there has been no chemotherapy or other targeted therapies to treat a relapse, and there is no evidence of Graft Versus Host Disease (GVHD). Donor leukocyte infusion is allowed provided there is no evidence of hematologic relapse as defined by the International Working Group (IWG) [12]

3. Subject's peripheral blast count does not exceed 30,000/microlitre before randomization into the study. Hydroxyurea treatment or leukapheresis may be used prior to or during the screening period to achieve this - see Section 6.7.2.

4. Subject's life expectancy at randomization is judged to be at least 3 months

5. Subjects should have recovered from the adverse effects of prior therapies to grade ≤1 (according to CTCAE v3) (excluding alopecia and any adverse effects that are expected to be chronic and stable)

6. Subjects must have had a bone marrow aspiration performed within 28 days prior to randomization showing the subject has at least 5% blasts and is therefore neither in CR nor CRp. This may be done at the Screening Visit if appropriate and feasible

7. Subjects must have adequate hepatic and renal function including the following:

   1. Total bilirubin ≤ 1.5 x upper limit of normal (in the absence of Gilbert's syndrome)
   2. AST and ALT ≤ 2.5 x upper limit of normal
   3. Serum creatinine ≤ 1.5 x upper limit of normal

8. Age ≥ 60 years

9. Performance status ≤ 2 (ECOG scale)

10. Screening left ventricular ejection fraction (LVEF) ≥ 50%

11. Subject is able to comply with all study procedures during the study including all visits and tests

12. Male subjects with female partners of reproductive potential must use acceptable contraceptive methods for the duration of time on study and continue to do so for a further 3 months after the end of tosedostat treatment

Exclusion:

1. Subjects who have received prior therapy for first relapse or refractory disease (a second induction cycle within a single induction regimen is allowed as defined above in Inclusion criterion 2)

2. Anti-cancer therapy including chemotherapy, radiotherapy, endocrine therapy, immunotherapy or use of any other investigational agents within 2 weeks prior to randomization (with the exception of hydroxyurea which can be used in certain circumstances. Section 6.7.2)

3. Subjects with APL (FAB type M3) or CML in blast crisis

4. Any prior or co-existing medical condition that in the Investigator's judgment will substantially increase the risk associated with the subject's participation in the study

5. Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary study procedures

6. Significant* cardiovascular disease defined as:

   1. Congestive heart failure NYHA class 4
   2. Unstable angina pectoris
   3. History of myocardial infarction within 6 months prior to study entry
   4. Presence of clinically significant valvular heart disease
   5. Uncontrolled or clinically significant ventricular arrhythmia
   6. Presence of clinically significant conduction defect on screening ECG
   7. Uncontrolled hypertension (i.e., systolic BP >160mmHg, diastolic >90 mmHg in repeated measurements) despite adequate therapy
   8. Clinically significant atrial fibrillation *Grade 3/4 in the CTCAE v3 grading would generally be considered clinically significant, although this remains a judgment for the Investigator to make.

7. Gastrointestinal disorders that may interfere with absorption of drug

8. Active serious infection or sepsis at randomization

9. Clinically significant interstitial lung disease