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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

Phase 2
60 Years
Not Enrolling
Acute Myeloid Leukemia, AML

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Trial Information

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

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 Criteria


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

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


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

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

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

The primary objective of the study is to evaluate the efficacy of tosedostat in elderly subjects with treatment refractory or relapsed AML by measuring CR and CRp.

Outcome Time Frame:

Months 1, 2, 3 & 6

Safety Issue:


Principal Investigator

Jorge E Cortes, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

M.D. Anderson Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

October 2009

Completion Date:

March 2011

Related Keywords:

  • Acute Myeloid Leukemia
  • AML
  • Acute Myeloid Leukemia
  • AML
  • Cancer
  • Hematological malignancies
  • Elderly
  • Refractory
  • Relapsed
  • Blood disorder
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid



MD Anderson Cancer CenterHouston, Texas  77030-4096
UCLA School of MedicineLos Angeles, California  900121973
Memorial Sloan-Kettering Cancer CenterNew York, New York  10021
Washington Cancer InstituteWashington, District of Columbia  20010
Froedtert HospitalMilwaukee, Wisconsin  53226-3596
University of Chicago Medical CenterChicago, Illinois  60637
M.D. Anderson Cancer Center OrlandoOrlando, Florida  32806
Stony Brook University Medical CenterStony Brook, New York  11794
Monter Cancer CenterLake Success, New York  11042
University of Michigan Health SystemAnn Arbor, Michigan  
Weill Cornell Medical College - New York Presbyterian HospitalNew York, New York  10021
Taussig Cancer InstituteCleveland, Ohio  
Duke Univeristy Medical CenterDurham, North Carolina  27710
Emory University ClinicAtlanta, Georgia  30322
Washington University, Oncology/Bone Marrow TransplantSt Louis, Missouri  63110
John Theurer Cancer Center, Hackensack University Medical Center,Hackensack, New Jersey  07601
Montefiore Medical Center Weiler DivisionBronx, New York  10461