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3821 Very High Rates of Clinical and Cytogenetic Response with the Combination of the Histone Deacetylase Inhibitor Pracinostat (SB939) and 5-Azacitidine in High-Risk Myelodysplastic Syndrome

Program: Oral and Poster Abstracts
Session: 633. Myelodysplastic Syndromes: Poster III
Monday, December 10, 2012, 6:00 PM-8:00 PM
Hall B1-B2, Level 1, Building B (Georgia World Congress Center)

Alfonso Quintás-Cardama, M.D.1*, Hagop M. Kantarjian, MD2, Farhad Ravandi3*, Cielo Foudray3*, Naveen Pemmaraju3*, Tapan M. Kadia, M.D.4, Gautam Borthakur, M.D.1, Naval G. Daver, MD4, Stefan Faderl, MD1, Elias Jabbour5*, Jorge E. Cortes, MD3 and Guillermo Garcia-Manero, MD1

1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2MD Anderson Cancer Center, Houston, TX
3Leukemia, MD Anderson Cancer Center, Houston, TX
4Department of Leukemia, The University of Texas, M. D. Anderson Cancer Center, Houston, TX
5Leukemia Department, The University of Texas M.D. Anderson Cancer Center, Houston, TX

Background

Pracinostat (SB939) is a dialkyl benzimidazole competitive inhibitor of histone deacetylase (HDACi) that has >1000-fold selectivity for HDAC Class 1 and 2 versus Class 3. Antitumor activity has been demonstrated in xenograft models of AML (MV4-11). We conducted a phase I study with pracinostat in patients with advanced myelodysplastic syndrome (MDS; n=11), acute myeloid leukemia (AML; n=12), and lymphoma (n=1). Pracinostat demonstrated excellent PK properties and target inhibition and was generally well tolerated. The MTD was not reached. Activity was documented in 9 patients (1 CR, 1 PR, 7 SD), which encouraged further exploration of pracinostat-based combinations. The recommended phase II dose was 100 mg daily. The combination of 5-azacitidine and HDACi is known to be safe and active in MDS and AML.

Methods

Ñ This is a pilot phase II study conducted as an extension study in the context of a phase I trial of pracinostat in hematological malignancies to determine the efficacy and safety of the combination of pracinostat (60 mg orally every other day 3 times a week for 3 consecutive weeks) and 5-azacitidine (75 mg/m2 IV daily x 5 every 3 to 6 weeks) given in 4-week cycles to patients with intermediate-2 or high risk MDS.

Results

Nine patients (6 women) were accrued between May 2011 and September 2011. Median age was 64 years (range, 22-73), WBC 2.4x109/dL (0.7-9.3), Hg 10g/dL (8.2-11), platelets 31x109/dL (14-269), and bone marrow blasts 7% (0%-18%). Seven (78%) patients had therapy related MDS with history of prior chemotherapy/radiotherapy exposure (3 breast cancer, 2 non-HodgkinÕs lymphoma, 1 breast and ovarian cancer, and 1 melanoma). Three patients had failed prior therapy: decitabine and haploidentical stem cell transplantation (SCT; n=1), lenalidomide (n=1), and decitabine and TXA-127 (n=1). All patients carried cytogenetic abnormalities: complex (n=4, 3 including -7 and 1 with -5), -7 (n=3, one of them with +8), t(6;9) (n=1), and t(14;16) and del(20) (n=1). Two patients with -7 also carried gene mutations: 1 in CEBPa and 1 IDH2R140Q. Patients received a median of 4 cycles. All 9 patients are evaluable. The overall response rate (ORR; defined as CR+CRi+PR) is 8/9 (89%) and the CR+CRi rate is 7/9 (78%). Five (56%) patients achieved a complete cytogenetic response, including the patient carrying IDH2R140Q, in whom such mutation became undetectable. Eight-week mortality was 0%. Only 1 (11%) patient has died, unrelated to study drug (after allogeneic-SCT). The median duration of response was 45 days (0-229). Reasons for discontinuation were: transition to allogeneic-SCT (n=5), no pracinostat availability by sponsor (n=2), no response (n=1), and progression to AML (n=1). The combination was well tolerated. All toxicities were grade 1 or 2. The most frequent toxicities were fatigue and nausea (56% each).

Conclusion

The combination of pracinostat and 5-azacitidine was very well tolerated in patients with MDS. The preliminary ORR of 89% is very encouraging, considering that most patients in this study had high-risk cytogenetics and/or had treatment related MDS, both subsets of MDS with very poor prognosis.

Disclosures: Ravandi: Celgene: Honoraria, Research Funding. Faderl: Genzyme: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Garcia-Manero: SBIO: Research Funding.

*signifies non-member of ASH