Vorinostat in Advanced Prostate Cancer Patients Progressing on Prior Chemotherapy (National Cancer Institute Trial 6862) Trial Results and Interleukin-6 Analysis: A study by the Department of Defense Prostate Cancer Clinical Trial Consortium and University of Chicago Phase 2 Consortium

Department of Medicine and Urology, University of Michigan, Ann Arbor, Michigan, USA.
Cancer (Impact Factor: 4.89). 09/2009; 115(23):5541-9. DOI: 10.1002/cncr.24597
Source: PubMed


This phase 2 trial was designed to evaluate the efficacy of vorinostat in chemotherapy-pretreated patients with metastatic castration-resistant prostate cancer.
Patients with disease progression on 1 prior chemotherapy, a prostate-specific antigen (PSA) >or=5 ng/mL, and adequate organ function were treated with 400 mg vorinostat orally daily. The primary endpoint was the 6-month progression rate. Secondary endpoints included safety, rate of PSA decline, objective response, overall survival, and effects of vorinostat on serum interleukin-6 (IL-6) levels.
Twenty-seven eligible patients were accrued. The median number of cycles delivered was 2 (range, 1-7). All patients were taken off therapy before 6 months. The best objective response in the eligible patient was stable disease in 2 (7%) patients. No PSA decline of >or=50% was observed. There was 1 grade 4 adverse event (AE), and 44% of patients experienced grade 3 adverse events. The most common adverse events were fatigue (81%), nausea (74%), anorexia (59%), vomiting (33%), diarrhea (33%), and weight loss (26%). Median time to progression and overall survival were 2.8 and 11.7 months, respectively. Median IL-6 levels (pg/mL) were higher in patients removed from the protocol for toxicity compared with progression at all time points, including baseline (5.2 vs 2.1, P = .02), Day 15 Cycle 1 (9.5 vs 2.2, P = .01), Day 1 Cycle 2 (9.8 vs 2.2, P = .01), and end of study (11.0 vs 2.9, P = .09).
Vorinostat at this dose was associated with significant toxicities limiting efficacy assessment in this patient population. The significant association between IL-6 levels and removal from the study for toxicities warrants further investigation.

Download full-text


Available from: Glenn Liu,
  • Source
    • "In experimental models, IL-6 showed induction of cancer stem cells and epithelial-mesenchimal transition phenotype, which are possible condition for resistance to the anti-HER-2 compounds trastuzumab and lapatinib [36,37]. High IL-6 levels showed association with toxicity from Vorinostat in prostate cancer patients [38]. Anti-IL-6 molecules may counteract this, and other detrimental effects enhanced by the up-regulation of the IL-6 system. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: IL-6 triggers oncogenic/angiogenic signals and the cytokine-dependent pro-cachexia cascade. The prognostic role of the functional IL-6 (promoter) rs1800795 and the IL-6R (receptor) rs8192284 single nucleotide polymorphisms (SNP) was studied in patients with advanced gastric cancer treated with palliative chemotherapy. Methods: One-hundred-sixty-one patients were genotyped for rs1800795 and rs8192284 SNPs using polymerase chain reaction based restriction fragment length polymorphism (PCR-RFLP) analysis assay. These results were studied for association with overall survival (OS). Results: In 161 assessable patients, frequencies of rs1800795 G/G, G/C and C/C genotypes were 46%, 42% and 12%, respectively. Frequencies of rs8192284 A/A, A/C and C/C genotypes were 36%, 45% and 19%, respectively. Carriers of the rs1800795 G/G and rs8192284 C/C genotypes showed the worst OS. In the multivariate model, rs1800795 G/G (1.69 hazard ratio; 95% confidence interval 1.18-2.42), and rs8192284 C/C (1.78 hazard ratio; 95% confidence interval 1.12-2.83) confirmed an adverse prognostic impact. Conclusions: In this population, genetic variants that up-regulate the IL-6 system showed impact on OS. This findings sustain the hypothesis that anti-IL-6 compounds deserve clinical studies as novel therapeutics in the palliative treatment of cancer patients.
    BMC Cancer 05/2014; 14(1):357. DOI:10.1186/1471-2407-14-357 · 3.36 Impact Factor
  • Source
    • "This leads to the formation of multiprotein complexes involved in the AR mediated transcriptional regulation of various genes implicated in prostate cancer growth and proliferation [40]. In prostate cancer, HDAC inhibition leads to decreased proliferation of cell lines and decreased tumor growth in preclinical models [41]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Androgen deprivation therapy (ADT) with medical or surgical castration is the mainstay of therapy in men with metastatic prostate cancer. However, despite initial responses, almost all men eventually develop castration refractory metastatic prostate cancer (CRPC) and die of their disease. Over the last decade, it has been recognized that despite the failure of ADT, most prostate cancers maintain some dependence on androgen and/or androgen receptor (AR) signaling for proliferation. Furthermore, androgen independent molecular pathways have been identified as drivers of continued progression of CRPC. Subsequently, drugs have been developed targeting these pathways, many of which have received regulatory approval. Agents such as abiraterone, enzalutamide, orteronel (TAK-700), and ARN-509 target androgen signaling. Sipuleucel-T, ipilimumab, and tasquinimod augment immune-mediated tumor killing. Agents targeting classic tumorogenesis pathways including vascular endothelial growth factor, hepatocyte growth factor, insulin like growth factor-1, tumor suppressor, and those which regulate apoptosis and cell cycles are currently being developed. This paper aims to focus on emerging molecular pathways underlying progression of CRPC, and the drugs targeting these pathways, which have recently been approved or have reached advanced stages of development in either phase II or phase III clinical trials.
    05/2013; 2013(5, supplement 98):981684. DOI:10.1155/2013/981684
  • Source
    • "This is especially telling with the epigenetic agents already approved for hematologic malignancies like MDS and CTCL. Vorinostat has been tested as a single agent in head and neck, breast, colorectal, and prostate cancer trials,102–104 and has not shown efficacy. A phase II trial with 94 non-small-cell lung cancer patients did not show significantly improved progression-free or overall survival, with 41% of patients unable to complete the six-cycle regimen.105 "
    [Show abstract] [Hide abstract]
    ABSTRACT: The emergence of epigenetic mechanisms as key regulators of gene expression has led to dramatic advances in understanding cancer biology. Driven by complex layers that include aberrant DNA methylation and histone modification, epigenetic aberrations have emerged as critical processes that disrupt cellular machinery and homeostasis. Recent discoveries have already translated into successful clinical trials and improved patient care, with several agents approved for hematologic disease and others undergoing study. As the field matures, substantial challenges persist that will require resolution. These include the need to decipher more fully the interplay between the epigenetic and genetic machinery, patient selection and improving treatment efficacy in solid tumors, and optimizing combination therapies to counteract chemoresistance and minimize adverse effects. Here, we review recent progress in epigenetic treatments and consider their implications for future cancer therapy.
    OncoTargets and Therapy 03/2013; 6:223-32. DOI:10.2147/OTT.S34680 · 2.31 Impact Factor
Show more