The OPAL Study: A Phase II Study to Evaluate the Efficacy, Safety and Tolerability of Tosedostat (CHR-2797) in Elderly Subjects With Treatment Refractory or Relapsed Acute Myeloid Leukemia

Inclusion Criteria

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