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Investigational New Drugs Aug 2015SB939 is a potent oral inhibitor of class 1, 2, and 4 histone deacetylases (HDACs). These three HDAC classes are highly expressed in castration resistant prostate cancer...
BACKGROUND
SB939 is a potent oral inhibitor of class 1, 2, and 4 histone deacetylases (HDACs). These three HDAC classes are highly expressed in castration resistant prostate cancer (CRPC) and associated with poor clinical outcomes. We designed a phase II study of SB939 in men with metastatic CRPC.
METHODS
Patients received SB939 60 mg on alternate days three times per week for 3 weeks on a 4-week cycle. Primary endpoints were PSA response rate (RR) and progression-free survival (PFS). Secondary endpoints included objective response rate and duration; overall survival; circulating tumor cell (CTC) enumeration and safety. Exploratory correlative studies of the TMPRSS2-ERG fusion and PTEN biomarkers were also performed.
RESULTS
Thirty-two patients were enrolled of whom 88 % had received no prior chemotherapy. The median number of SB939 cycles administered was three (range 1-8). Adverse events were generally grade 1-2, with five pts experiencing one or more grade three event. One patient died due to myocardial infarction. A confirmed PSA response was noted in two pts (6 %), lasting 3.0 and 21.6 months. In patients with measurable disease there were no objective responses. Six patients had stable disease lasting 1.7 to 8.0 months. CTC response (from ≥5 at baseline to <5 at 6 or 12 weeks) occurred in 9/14 evaluable patients (64 %).
CONCLUSION
Although SB939 was tolerable at the dose/schedule given, and showed declines in CTC in the majority of evaluable patients, it did not show sufficient activity based on PSA RR to warrant further study as a single agent in unselected patients with CRPC.
Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Benzimidazoles; Disease-Free Survival; Histone Deacetylase Inhibitors; Humans; Kallikreins; Male; Middle Aged; Neoplastic Cells, Circulating; PTEN Phosphohydrolase; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Serine Endopeptidases; Trans-Activators; Transcriptional Regulator ERG
PubMed: 25983041
DOI: 10.1007/s10637-015-0252-4 -
Annals of Oncology : Official Journal... May 2015A subgroup of sarcomas is characterized by defining chromosomal translocations, creating fusion transcription factor oncogenes. Resultant fusion oncoproteins associate...
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.
Topics: Administration, Oral; Adult; Antineoplastic Agents; Benzimidazoles; Biomarkers, Tumor; Canada; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Early Termination of Clinical Trials; Female; Histone Deacetylase 2; Histone Deacetylase Inhibitors; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Sarcoma; Time Factors; Translocation, Genetic; Treatment Outcome; Young Adult
PubMed: 25632070
DOI: 10.1093/annonc/mdv033 -
Leukemia Apr 2015Acute myeloid leukemia (AML) is the second most common form of leukemia and the most frequent cause of leukemia-related deaths in the United States. The incidence of AML... (Review)
Review
Acute myeloid leukemia (AML) is the second most common form of leukemia and the most frequent cause of leukemia-related deaths in the United States. The incidence of AML increases with advancing age and the prognosis for patients with AML worsens substantially with increasing age. Many older patients are ineligible for intensive treatment and require other therapeutic approaches to optimize clinical outcome. To address this treatment gap, novel agents with varying mechanisms of action targeting different cellular processes are currently in development. Hypomethylating agents (azacitidine, decitabine, SGI-110), histone deacetylase inhibitors (vorinostat, pracinostat, panobinostat), FMS-like tyrosine kinase receptor-3 inhibitors (quizartinib, sorafenib, midostaurin, crenolanib), cytotoxic agents (clofarabine, sapacitabine, vosaroxin), cell cycle inhibitors (barasertib, volasertib, rigosertib) and monoclonal antibodies (gentuzumab ozogamicin, lintuzumab-Ac225) represent some of these promising new treatments. This review provides an overview of novel agents that have either completed or are currently in ongoing phase III trials in patients with previously untreated AML for whom intensive treatment is not an option. Other potential drugs in earlier stages of development will also be addressed in this review.
Topics: Age Factors; Aged; Antibodies, Monoclonal; Antimetabolites, Antineoplastic; Antineoplastic Agents; Clinical Trials, Phase III as Topic; Cytotoxins; Drugs, Investigational; Histone Deacetylase Inhibitors; Humans; Leukemia, Myeloid, Acute; Patient Selection; Protein Kinase Inhibitors
PubMed: 25142817
DOI: 10.1038/leu.2014.244 -
Leukemia Research Aug 2014
Topics: Animals; Antineoplastic Agents; Benzimidazoles; Drug Discovery; Epigenesis, Genetic; Flavonoids; Histone Deacetylase Inhibitors; Humans; Leukemia, Myeloid, Acute; Orphan Drug Production; Piperidines; Protein Kinase Inhibitors; Pteridines; Terminology as Topic
PubMed: 24996975
DOI: 10.1016/j.leukres.2014.06.007