Q S-C Chu1, T O Nielsen2, T Alcindor3, A Gupta4, M Endo5, A Goytain2, H Xu6, S Verma7, R Tozer8, M Knowling2, V B Bramwell9, J Powers6, L K Seymour6, E A Eisenhauer6. 1. Division of Medical Oncology, Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton quincy.chu@albertahealthservices.ca. 2. Department of Pathology, British Columbia Cancer Agency, Vancouver. 3. Division of Medical Oncology, Department of Oncology, McGill University, Montreal. 4. Division of Medical Oncology, Department of Oncology, Mount Sinai Hospital/Princess Margaret Hospital, University of Toronto, Toronto, Canada. 5. Department of Orthopedic Surgery, Kyushu University, Fukuoka, Japan. 6. Investigational New Drug Program, NCIC-Clinical Trials Group, Kingston. 7. Department of Medical Oncology, Ottawa Cancer Centre, University of Ottawa, Ottawa. 8. Division of Medical Oncology, Department of Oncology, Jurvinski Cancer Centre, McMaster University, Hamilton. 9. Division of Medical Oncology, Department of Oncology, Tom Baker Cancer Centre, University of Calgary, Calgary, Canada.
Abstract
BACKGROUND: A subgroup of sarcomas is characterized by defining chromosomal translocations, creating fusion transcription factor oncogenes. Resultant fusion oncoproteins associate with chromatin-modifying complexes containing histone deacetylases (HDAC), and lead to epigenetic transcriptional dysregulation. HDAC inhibitors were shown to be effective in vitro, reversing gene repression by these complexes, restoring PTEN expression and apoptosis via the PI3K/Akt/mTOR pathway. PATIENTS AND METHODS: SB939 is an oral inhibitor of classes 1 and 2 HDAC. Eligible patients with recurrent or metastatic translocation-associated sarcoma (TAS) by local pathology were treated with 60 mg/day every other day for 3 of 4 weeks. Central pathology review was conducted with fusion oncogenes characterized, and HDAC2 expression correlated with efficacy in pre-specified methods. RESULTS: Twenty-two patients were treated with a median of 2 cycles. Fourteen patients were assessable for response with confirmed specific chromosomal translocations; 8 had a best response of stable disease (SD) (median duration 5.4 months) with no confirmed objective responses. The 3-month progression-free survival (PFS) rate was 49%. Among those with HDAC2 score ≥5, 7/10 had SD, versus 0/3 with HDAC2 score <5. SB939 was considered as well tolerated with <10% patients experienced ≥grade 3 toxicity. CONCLUSION: This study was stopped prematurely due to prolonged unavailability of SB939. No objective responses were seen. Although the observed SD in HDAC2 high patients was interesting, due to the small sample size, no definitive conclusion can be drawn about the efficacy of SB939 in this patient population. CLINICAL TRIAL: NCT01112384.
BACKGROUND: A subgroup of sarcomas is characterized by defining chromosomal translocations, creating fusion transcription factor oncogenes. Resultant fusion oncoproteins associate with chromatin-modifying complexes containing histone deacetylases (HDAC), and lead to epigenetic transcriptional dysregulation. HDAC inhibitors were shown to be effective in vitro, reversing gene repression by these complexes, restoring PTEN expression and apoptosis via the PI3K/Akt/mTOR pathway. PATIENTS AND METHODS: SB939 is an oral inhibitor of classes 1 and 2 HDAC. Eligible patients with recurrent or metastatic translocation-associated sarcoma (TAS) by local pathology were treated with 60 mg/day every other day for 3 of 4 weeks. Central pathology review was conducted with fusion oncogenes characterized, and HDAC2 expression correlated with efficacy in pre-specified methods. RESULTS: Twenty-two patients were treated with a median of 2 cycles. Fourteen patients were assessable for response with confirmed specific chromosomal translocations; 8 had a best response of stable disease (SD) (median duration 5.4 months) with no confirmed objective responses. The 3-month progression-free survival (PFS) rate was 49%. Among those with HDAC2 score ≥5, 7/10 had SD, versus 0/3 with HDAC2 score <5. SB939 was considered as well tolerated with <10% patients experienced ≥grade 3 toxicity. CONCLUSION: This study was stopped prematurely due to prolonged unavailability of SB939. No objective responses were seen. Although the observed SD in HDAC2 high patients was interesting, due to the small sample size, no definitive conclusion can be drawn about the efficacy of SB939 in this patient population. CLINICAL TRIAL: NCT01112384.
Authors: Marieke A de Graaff; Jamie S E Yu; Hannah C Beird; Davis R Ingram; Theresa Nguyen; Jeffrey Juehui Liu; Svetlana Bolshakov; Károly Szuhai; Pierre Åman; Keila E Torres; Dina Lev; Torsten O Nielsen; Judith V M G Bovée; Alexander J Lazar; Neeta Somaiah Journal: Lab Invest Date: 2016-06-06 Impact factor: 5.662