Impact of Vorinostat on Pruritus Signaling Pathways - Merck Study
This study has been withdrawn prior to enrollment.
(Enrollment was too slow, so no participants were ever enrolled.)
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
First received: February 25, 2013
Last updated: January 26, 2015
Last verified: January 2015
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.
||Observational Model: Cohort
Time Perspective: Prospective
||A Phase IV Study Of The Impact Of Vorinostat On Cellular Signaling And Cytokine Production In Cutaneous T-Cell Lymphoma Patients With Pruritus
Primary Outcome Measures:
- the percentage change in pSTAT3 expression among patients reporting a relief in their pruritus, irrespective of lesion clearing [ Time Frame: 6 months ] [ Designated as safety issue: No ]
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 pruritus on a visual analogue score (VAS) from 0-100 mm (0, none; 100, worst imaginable). Meaningful change in pruritus is 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).
Spearman rank correlation will examine the significance of the association between the change in cytoplasmic staining intensity 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 descriptive purposes only, analyses will also be performed stratified on pruritis stage at baseline (early stage I-IIA vs. late stage IIB-IVB and pruritus, mild VAS less than 40 vs. moderate to severe VAS greater than 40, up to 100).
Biospecimen Retention: Samples With DNA
Secondary Outcome Measures:
- IL-31 amount and intensity of cathepsin S expression [ Time Frame: 6 months ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: No ]
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.
Blood Samples Skin biopsies
| Study Start Date:
| Estimated Study Completion Date:
| Primary Completion Date:
||January 2015 (Final data collection date for primary outcome measure)
MF patients for blood & biopsy
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. Vorinostat (Zolinza) will be administered as follows: each subject will receive each month for the first 3 months (cycle 1 to 3) 3 capsules of vorinostat 100 mg po daily. For months 4-6 (cycles 4 to 6), subjects will receive each month for 4 capsules of vorinostat 100 mg po daily.
Two 6 mm skin punch biopsies (one from pruritic skin and from involved non pruritic skin).
Peripheral blood (10 mls) to be drawn and used for cytokine analysis.
|Ages Eligible for Study:
||18 Years to 85 Years (Adult, Senior)
|Genders Eligible for Study:
|Accepts Healthy Volunteers:
Subjects with CTCL-mycosis fungoides type treated at Boston Medical Center and that have, independent of this study, already agreed to start vorinostat according to the stand-of-care guidelines.
- 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
- 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
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01801670
|Boston, Massachusetts, United States, 02118 |
Merck Sharp & Dohme Corp.
||Deon Wolpowitz, MD, PhD
History of Changes
|Other Study ID Numbers:
|Study First Received:
||February 25, 2013
||January 26, 2015
||United States: Food and Drug Administration
Keywords provided by Boston University:
cutaneous T-cell lymphoma
Additional relevant MeSH terms:
ClinicalTrials.gov processed this record on July 21, 2016
Lymphoma, T-Cell, Cutaneous
Neoplasms by Histologic Type
Immune System Diseases
Signs and Symptoms
Histone Deacetylase Inhibitors
Molecular Mechanisms of Pharmacological Action