Clinical Trial: Impact of Vorinostat on Pruritus Signaling Pathways - Merck Study

Study Status: Withdrawn
Recruit Status: Withdrawn
Study Type: Observational

Official Title: A Phase IV Study Of The Impact Of Vorinostat On Cellular Signaling And Cytokine Production In Cutaneous T-Cell Lymphoma Patients With Pruritus

Brief Summary: Mycosis Fungoides (MF) is a rare malignancy in the United States. It is the most common form of cutaneous T-cell lymphoma (CTCL). Sézary syndrome (SS) is the most severe and leukemic form of CTCL. Pruritus, or itch, is defined as an unpleasant sensation that elicits the desire to scratch. Severe itch is a manifestation of all forms of MF, especially those with patch/plaque and folliculotropic variants, as well as in Sezary patients. While severe itch causes great suffering for patients, the pathogenesis of itch in MF and Sezary syndrome is complex and not well understood. It is thought that various chemical mediators are produced by the malignant cells to cause itch. Vorinostat, an FDA approved therapy for the treatment of MF, has also been reported to relieve pruritis. The goal of the study is to evaluate how vorinostat affects different chemicals in the skin that have been known to cause itch. This is a single center, non-randomized study designed to obtain and test blood and skin tissue samples take at various time-points over 6 months in patients who are prescribed vorinostat per standard of care treatment. Samples from pruritic and non-pruritic skin and blood of MF and Sezary patients will be evaluated for the presence of chemicals thought to be important in the cause of itch in these diseases. This evaluation will include immunohistochemistry, RT-PCR, and ELISA assays. The results from this study may help define how vorinostat decreases itch in patients with MF and Sezary Syndrome.

Detailed Summary:

Mycosis Fungoides (MF) is a rare malignancy in the United States. It is the most common form of cutaneous T-cell lymphoma (CTCL). Sézary syndrome (SS) is the most severe and leukemic form of CTCL. Severe pruritus is a manifestation of the SS and also affects patients with MF. Severe pruritus is a manifestation of SS and also a common symptom among patients with MF. Pruritus can significantly impact on quality of life. In one national survey of the impact of MF on patients' health-related quality of life (HRQOL), the majority of survey respondents (88%) reported being bothered by pruritus.

The pathogenesis of pruritus is complex and not well understood. It affects a majority of patients with mycosis fungoides (MF) and is most severe in Sézary syndrome (SS), the leukemic form of cutaneous T-cell lymphoma. Chemical or physical stimuli that perturb, without damaging, only the epidermis (the outer most layer of the skin), elicit the symptom of pruritus. The perception of itch is abolished if the epidermis is removed. This observation and the data on PAR2 expression on nerve fibers indicate that pruritus in inflammatory skin disorders including MF/SS is likely to have a neuroepidermal origin or be mediated by molecules that percolate to the epidermis from inflammatory cells in the dermis. In this regard, MF/SS are characterized histologically by infiltration of the epidermis by neoplastic T cells (epidermotropism), and in some of these cases, the neoplastic cells form collections of 2-3 cells around epidermal Langerhans cells (Pautrier microabscess). Neoplastic cells of advanced MF/SS typically are polarized to secrete TH2 cytokines. It has been hypothesized that the accumulation of neoplastic cells in skin lesions promotes a shift from a TH1 predominant cytokine profile in early MF to a TH2 predominant cytokine profile in advanced disease 4. The shift to TH2 producti
Sponsor: Boston University

Current Primary Outcome: the percentage change in pSTAT3 expression among patients reporting a relief in their pruritus, irrespective of lesion clearing [ Time Frame: 6 months ]

Original Primary Outcome: Same as current

Current Secondary Outcome:

• IL-31 amount and intensity of cathepsin S expression [ Time Frame: 6 months ]

  IL31 amount and cathepsin S intensity of expression will be determined at 3 time points described above and also from itchy and non-itchy skin at each time point. The goal is to determine if there is an association between a change (presumably a decrease) in these targets and an improvement in pruritus as reported by the VAS score.

  Spearman rank correlation will examine the significance of the association between the change in amount of IL-31 or level of cathepsin S expression and change in pruritus as assessed by subjects with the visual analog scale, neither of which will be assumed to follow a Gaussian distribution.

  For this data, taken in separate locations (treatment, control) on the same individuals, we will perform paired t-tests or non-parametric Wilcoxon signed rank tests as appropriate.

• percentage of vasodilatory peptidergic nerves at the dermoepidermal junction as a percentage of total nerves [ Time Frame: 6 months ]

  The total nerve length of all nerves and the total nerve length of nerves expressing vasodilatory peptidergic markers will be determined in the skin biopsies at 3 time points described above, and the percentage calculated.

  Spearman rank correlation will examine the significance of the association between the change in the above percentage of nerves and change in pruritus as assessed by subjects with the visual analog scale, neither of which will be assumed to follow a Gaussian distribution.

  For this data taken in separate locations (treatment, control) on the same individuals, we will perform paired t-tests or non-parametric Wilcoxon signed rank tests as appropriate.

Original Secondary Outcome: Same as current

Information By: Boston University

Dates:
Date Received: February 25, 2013
Date Started: January 2015
Date Completion: January 2015
Last Updated: January 26, 2015
Last Verified: January 2015