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These data suggest that cancer-specific inhibitors of Fas such asPMLRAR� block Fas-mediated apoptosis and thus can contribute toancer development and resistance to therapy. Our results may pro-ide an explanation for the long-known role of PMLRAR� and PMLn the regulation of Fas signaling, which we have shown to occur byirect regulation. We have identified an attractive potential target tohe regulation of apoptosis at the PMLRAR�-Fas and PML-Fas in-

terfaces. By neutralizing the effect of death receptor inhibitors such asPMLRAR� and other potential inhibitors, we can improve on thesuccess of the many chemotherapeutic treatments that depend onactivation of death receptors for effective elimination of cancer cells.

509The OPAL Study: A Phase II Study to Evaluate theEfficacy, Safety and Tolerability of Tosedostat(CHR-2797) in Elderly Subjects with TreatmentRefractory or Relapsed Acute MyeloidLeukemiaJorge Cortes,1 Eric Feldman,2 Karen Yee,3 Martin

oal,4 Alison Richardson,4 Anthony Charman,4 NicoFlores4

1The University of Texas MD Anderson Cancer Center, 2Weil-

Cornell Medical College, 3Princess Margaret Hospital, 4Chroma

Therapeutics

Brief Abstract: Tosedostat is a novel oral aminopeptidase inhib-itor which targets malignant cells. A previous study showed promis-ing anti-leukemic effects in AML. The current study examines tose-dostat in relapsed/refractory AML patients who attained a firstremission lasting less than a year. Study recruitment has now com-pleted and the population will be described. Full Abstract:Introduction: Tosedostat (CHR-2797) is a novel oral aminopepti-dase inhibitor (Krige et al, 2008) which leads to a deficiency of freeamino acids for new protein synthesis. Malignant cells appear to bemore dependent on protein cycling than normal cells. A previousphase I-II study (Lowenberg et al, JCO 2010) with tosedostat whichincluded thirty-five patients with relapsed or refractory AML showedpromising anti-leukemic affects based on bone marrow responsesand longer overall survival for responders compared to nonresponders. Methods: The OPAL study is a phase II study in 2 parts.Part A is a dose selection part in which 70 patients will be randomizedto receive tosedostat 120 mg daily for 6 months OR tosedostat 240mg daily for 2 months followed by 120 mg for 4 months. A benefit-risk analysis will take place to determine the dose for Part B in whicha further 130 patients will be treated with tosedostat. Responses willbe based on an evaluation of bone marrow and hematology usingIWG criteria (Cheson et al, 2003).Inclusion Criteria

● Age � 60 years.● Confirmed diagnosis of AML according to WHO classification

excluding APL) who have had either a first CR lasting less than 12onths, or have not had a first CR and who will receive their first

alvage therapy in this study (Estey, 1996).

Clinical Lymphoma, Myeloma & Leukemia June 2011

● Adequate hepatic and renal function, PS � 2, LVEF � 50%xclusion Criteria● Anti-cancer therapy including chemotherapy, radiotherapy, en-

ocrine therapy, immunotherapy or use of any other investigationalgents within 2 weeks prior to trial entry (with the exception ofydroxyurea)● Significant cardiovascular disease as defined in the protocol.

nrollment:Part A enrollment finished early Sept 2010. Baseline characteris-

ics of the study population will be presented, including demograph-cs, prior AML history, AML classification, baseline cytogenetics,rognostic category and duration of prior response.eferences:Krige et al, Cancer Res. 2008 Aug 15;68(16):6669-79.Lowenberg et al, J Clin Oncol, 28 published online 23-Aug-10Estey, Blood 88:756, 1996Cheson et al, J Clin Oncol 21:4642–4649, 2003

510Addition of All-Trans Retinoic Acid (ATRA) tothe Combination of Fludarabine, Cytarabine,Idarubicin, With or Without GCSF in Older,Higher Risk Patients with AML and High-RiskMDS Does Not Improve the Outcome in Thosewith NPM1 MutationAsifa Malik,1 Carlos Bueso-Ramos,1 Stefan Faderl,1

Eli Estey,2 Susan O’Brien,1 Michael Fernandez,1

Martin Nguyen,1 Charles Koller,1 Emil Freireich,1

Miloslav Beran,1 Sherry Pierce,1 Jorge Cortes,1

Hagop Kantarjian,1 Farhad Ravandi11The University of Texas MD Anderson Cancer Center, 2University

of Washington Seattle Cancer Care Alliance

Brief Abstract: The objective of our study was to examine thempact of the addition of ATRA among older, higher risk AML andigh-risk MDS patients with diploid cytogenetics treated with aombination of fludarabine � cytarabine � idarubicine �/� GCSF

�/� ATRA with known NPM1 mutation status enrolled on a ran-domized phase II study and to compare the differences in CR rate,EFS or OS with those patients who did not receive ATRA in additionto their chemotherapy. Full Abstract: Background: Previous studies

ave suggested that the mutations of the NPM1 gene may be aarker for response to all-trans retinoic acid ( ATRA) given as an

djunct to intensive chemotherapy in older patients with acute my-loid leukemia (AML) (Shlenk RF, Haematologica, 2009, 94, 54-0) but not younger patients (Burnett AK, Blood, 2010, 115,948).atients and Methods: We examined the impact of the addition ofTRA among patients with diploid cytogenetics treated on a ran-omized phase II study of fludarabine � cytarabine � idarubicine

�/� GCSF �/� ATRA with available data on their NPM1 muta-tion status. Between September 1995 and November 1997, 215patients were enrolled in the study. They had to have one of theunfavorable features of age � 71 years, antecedent hematological

disorder (AHD), therapy- related AML or MDS or high bilirubin