Impact of Vorinostat on Pruritus Signaling Pathways - Merck Study
Impact of Vorinostat on Pruritus Signaling Pathways - Merck Study
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.
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 production coincides with impaired immune responses,
 eosinophilia, and high levels of IgE in the blood. Severe pruritus is more frequent in
 patients with advanced MF/SS suggesting that tumor burden or cytokines elaborated by
 activated tumor cells may be correlated to intensity of pruritus.

 While it is not clear which cells contributed to the TH2 cytokine shift, studies of T-cells
 isolated from skin and blood of affected patients showed activation of the signaling
 molecule, STAT3. In CTCL lines, constitutively activated STAT3 mediates IL-5 production
 (principal regulator of eosinophilia) and IL-13 (favors antibody responses) 5. Moreover,
 IL-31 also seems to signal through STAT3 in one lung model. Current treatments of pruritus
 are aimed towards symptomatic relief although these do not address the mechanism of pruritus.
 If neoplastic cells are producing IL-31 or other pruritogenic factor as we propose, then any
 treatment that eliminates these cells will also be effective for pruritus. To date,
 effectively improving pruritus and the disease manifestations is not always possible
 especially in advanced MF or SS.

 Vorinostat is a FDA approved histone deacetylase inhibitor for the treatment of the cutaneous
 manifestations of patients with cutaneous T-cell lymphoma (MF/SS) who have progressive,
 persistent, or recurrent disease on or following 2 systemic therapies. Vorinostat induces
 differentiation, growth arrest, and/or apoptosis of malignant cells both in vitro and in vivo
 and has shown clinical responses in approximately 30% of patients with advanced MF/SS 7.
 Overall, 32% of patients with severe pruritus had relief of this symptom, and it was observed
 that the relief of pruritus often presaged the clinical response, especially in SS. This
 suggests to us that the gene modulating effects of vorinostat might be directly inhibiting
 expression of IL-31 or other cytokines that mediate pruritus in MF/SS. IL-31 appears to be
 implicated in pruritus of atopic dermatitis. 8 Recently, studies have demonstrated that itch
 can be mediated by a novel cysteine protease and that proteinase-activated receptor-2 plays
 an important role in itch signaling pathways. 9, 10 In another recent study, substance P has
 been implicated in itch pathophysiology. In one small case series of patients with CTCL, the
 efficacy of aprepitant was evaluated11. Aprepitant is a substance P antagonist that blocks
 the neurokinin 1 (NK1) receptor. Substance P has a role in the physiology of unmyelinated
 C-fibers in the skin that convey both pain and pruritus and has the ability to modulate mast
 cell functioning.

 Data from skin biopsies have shown that successful treatment with vorinostat is associated
 with decreased dermal and epidermal lymphocytes, a shift from nuclear to cytoplasmic p-STAT-3
 staining, and decreased CD31-positive dermal vessels. This was not confirmed in another
 study. Vorinostat has been postulated to indirectly inactivate STAT proteins that drive
 cellular proliferation and TH2 cytokine expression. Researchers observed that in skin
 biopsies of patients enrolled in the vorinostat stage IIB trial, nuclear accumulation of
 STAT1 and high levels of nuclear pSTAT3 in malignant T cells correlated with a lack of
 clinical response. To date, there has been no evaluation of STAT3 proteins and TH2 cytokines
 in pruritic versus non-pruritic skin lesions of CTCL. Signal transducers and activators of
 transcription (STATS) are important to active transcription of cellular proteins including
 cytokines. Constitutive activation of STATs has been shown to be a feature of MF/SS.

 Study Rationale:

 Since pruritus is a common manifestation of the disease that significantly impacts on
 patient's quality of life and that oral vorinostat provides clinical relief from pruritus in
 treated patients, understanding the mechanisms of action of vorinostat on cytokines
 implicated in pruritus will shed light on its therapeutic effect. In particular, because we
 believe that a reduction in pSTAT3 activity as evidenced by fewer and/or less strongly
 stained tumor cells may be taking place in patients responding to therapy and reporting
 decrease pruritus. Thus, understanding the extent of STAT3 protein aberration and cytokine
 expression (IL-31) in pruritic skin lesions could significantly contribute to our
 understanding of the mechanism of pruritus in MF/SS and to how vorinostat relieves this
 serious symptom.

 Objectives/Hypothesis It is hypothesized that skin tissue expression of pSTAT3, IL-31, and
 cathepsin S will correlate with response to vorinostat, a recently FDA approved therapy for
 MF and SS, decreasing in expression with relief of pruritus.

 Methods: Dosing and Frequency of Drug

 Participants who are cared for at Boston Medical Center will first be assessed by physicians
 of the CTCL multi-specialty clinic if vorinostat, administered per standard of care, is an
 appropriate therapy for their CTCL. The decision to invite patients to participate in this
 study is (1) separate from the above described clinical decision to utilize vorinostat, and
 (2) will be offered subsequent to the clinical decision to utilize vorinostat. There is no
 placebo group for this study. Up to ten participants are desired for this study.

 Three biopsies will be taken: (1) at baseline; (2) after 4 weeks of 300 mg daily vorinostat,
 and (3) if tolerated, after 4 more weeks of 400 mg daily vorinostat. At each time point, up
 to 2 biopsies will be taken depending on if 1 or both skin types are present (itchy vs
 non-itchy) at that time point and whether or not itchy or non-itchy skin shows a lesion. For
 each time point and each skin type, pSTAT3 staining will be measured as strong (2+), weak
 (1+), none (0). At each time point, patients will report the extent of their pruritus on a
 visual analogue score (VAS) from 0-100 mm (0, no pruritus; 100, worst imaginable pruritus).
 Meaningful change in pruritus will be a change in VAS score of 30 mm or more from baseline to
 the third time point (a change measure that will also be computed for all endpoints; the
 baseline to time 3 measure being of primary clinical interest).

 Sample Size/Accrual Rate: The total enrollment planned is 10 patients at a rate of 1-2
 patients per month. With 10 subjects, for our primary hypothesis (correlation of staining
 intensity with self-reported degree of pruritis) we can detect a Spearman rank correlation
 coefficient as small as 0.75 for a one-sided test with 80% power (a directional hypothesis
 that is reasonable) or one as small as 0.80 for a two-sided hypothesis. In each case, these
 coefficients are of clear clinical relevance and are plausible given the nature of the
 measures. For the hypothesis of equal changes between treated and control areas on the same
 individuals, we propose using paired data analyses such as paired t-tests and Wilcoxon rank
 sum tests. For a sample size of 10 and 80% power, a paired t-test can detect an effect size
 of 0.996 or greater for a two-sided test and an effect size of 0.853 or greater for a
 one-sided test. These effect sizes are large but are within reason to expect for a clinically
 effective treatment.
Inclusion Criteria:

 -  Patients w/ histologically confirmed mycosis fungoides stage IB to IVA eligible to
 receive oral vorinostat

 -  Patients w/ stage IB to IV reporting pruritus

 -  Patients age 18-85 years, of any race, sex, and ethnicity

 -  Life expectancy > 24 weeks

 -  Patient must have performance status of ≤2 on the ECOG Performance Scale

 -  Patients w/ a min. of 3 weeks since their last systemic treatment

 -  Women who are not pregnant, lactating, or of childbearing potential

 -  Female patients w/ reproductive potential must use an adequate contraceptive method
 during treatment and for three months after completing treatment

 -  Male patient w/ reproductive potential, agrees to use an adequate method of
 contraception for the duration of the study and for 30 days beyond the duration of
 study

 -  Patients, or legal representative must to be willing to adhere to the protocol, and
 sign an Informed Patient Consent Form prior to entry into the study

 -  Patients must not be on any other investigational device/drug treatment for MF/SS

 -  Patient is available for periodic blood sampling, study related assessments, and
 management at the treating institution for the duration of the study

 -  Eligibility of patients receiving medications or substances known or with the
 potential to affect the activity or pharmacokinetics of vorinostat will be determined
 by the Principal Investigator

 -  Patient must have adequate organ function as indicated by laboratory values

 Exclusion Criteria:

 -  Patients w/ a recent cardiac history, such as a myocardial infarct within the last
 year, uncontrolled angina, severe uncontrolled ventricular arrhythmias, clinically
 significant pericardial disease, or electrocardiographic evidence of acute ischemic or
 active conduction system abnormalities

 -  Patients w/ a history of liver damage (2.5 x normal ALT, AST), leukopenia, or
 thrombocytopenia

 -  Women who are pregnant or nursing a child

 -  Patients w/ severe emotional, behavioral or psychiatric problems that, in the opinion
 of the investigator, would result in poor compliance with the treatment regimen

 -  Patients who have received and histone deacetylase inhibitor within the last 6 months

 -  Patients receiving valproic acid will be excluded unless there has been a wash-out
 period of 30 or more days

 -  Patients who will have received systemic therapy, radiation therapy or phototherapy
 within 3 weeks prior to initial dosing with study drugs or who has not recovered from
 adverse events due to agents administered more than 3 weeks earlier

 -  QTc prolongation greater than 500ms

 -  Patient w/ a "currently active" second malignancy, other than non-melanoma skin cancer
 and carcinoma in situ of the cervix, should not be enrolled

 -  Patients are not considered to have a "currently active" malignancy if they have
 completed therapy for a prior malignancy, are disease free from prior malignancies for
 >5 years or are considered by their physician to be at less than 30% risk of relapse

 -  Patient is on any systemic steroids that have not been stabilized during the 3 weeks
 prior to the start of the study drugs

 -  History of allergic reactions attributed to compounds of similar chemical or biologic
 composition to vorinostat

 -  Patient has known psychiatric or substance abuse disorders that would interfere with
 cooperation with the requirements of the trial

 -  Patient is, at the time of signing informed consent, a regular user of any illicit
 drugs, substance abuse or had a recent history (within last year) of drug or alcohol
 abuse

 -  Patient has uncontrolled intercurrent illness or circumstances that could limit
 compliance with the study, including, but not limited to: active infection, acute or
 chronic graft versus host disease, symptomatic congestive heart failure, unstable
 angina pectoris, cardiac arrhythmia, or psychiatric conditions

 -  Patient has a history or current evidence of any condition, therapy, or lab
 abnormality that might confound the results of the study, interfere with the patient's
 participation for the full duration of the study or is not in the best interest of the
 patient to participate

 -  HIV-positive patients will be ineligible

 -  Patients w/ known history of Hepatitis B or C are excluded