PUVA Maintenance Therapy in Mycosis Fungoides

Study Overview
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Brief Summary
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The purpose of the study is to determine whether psoralen plus UVA (PUVA) photochemotherapy maintenance treatment prolongs disease-free survival of cutaneous T cell lymphoma (mycosis fungoides) patients.

Detailed Description
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Background: Psoralen plus UVA (PUVA) photochemotherapy consists of the topical or oral application of psoralen, followed by exposure to UVA light. PUVA is used in various conditions, including early stages of mycosis fungoides (MF) and other primary and secondary lymphoproliferative disorders. PUVA has strong pro-apoptotic and immunomodulating properties, but the exact mechanisms by which PUVA leads to clearance of MF are not well understood. Although MF is generally a slowly progressing disease, it ultimately can spread to lymphoid tissues, peripheral blood, and other organs, leading to death. Previous Work: PUVA therapy is a well-accepted first-line treatment option for skin-limited MF (stages IA, IB, and IIA), leading to complete remission in a high portion of patients (approximately 70 to 90%). Long-term remissions can be achieved with PUVA in a certain percentage of patients. However, in most cases MF lesions relapse after stop of PUVA after variable time intervals with a median time to relapse of 14 to 17 month, according to our own experience. Not only is little is known about the therapeutic mechanisms of PUVA in MF but as little is known about optimal duration and frequency of treatment (2, 3, or 4 times weekly), dose escalation, and maintenance therapy. Although PUVA has been introduced more than 30 years ago, there is lack of prospective controlled studies with clearly defined dose schemes and also an ongoing controversy whether PUVA maintenance therapy may prolong disease remission in MF upon initial complete clearance. Hypothesis & Intended Work: We hypothesize that PUVA prolongs disease free survival in MF patients. In a randomized multicenter trial involving 9 centers in Austria, we plan to investigate (1) the clinical efficacy of PUVA and its maintenance therapy in MF and, (2) the mechanisms by which PUVA leads to disease clearance. In total, 82 patients will be enrolled and treated with a defined PUVA regimen with 2 exposures per week for 12 to 24 weeks. After 12 to 24 weeks of PUVA treatment, patients with complete remission will be randomized into two arms. In Arm A patients will be treated with PUVA maintenance therapy at constant single UVA doses. Maintenance treatment will be given once a week for one month (4 weeks), every 2 weeks for 2 months (8 weeks) and after three months once a month over 6 months. After 9 months of maintenance therapy patients will discontinue therapy. Patients in Arm B will receive no therapy. All patients will be followed until recurrence or at least 12 months (in non-recurrent patients) when the primary study analysis will be done. In addition, the follow-up will be extended to 60 months for long-term results. The mechanistic action of PUVA will be studied by laboratory investigations, including immune function and cytokine analysis. Outlook: A better understanding of the optimal regimen and the therapeutic mechanisms of PUVA in MF should help improving treatment strategies for this life-threatening disease. The understanding of the mode of action of PUVA in MF may also help to develop novel treatments using PUVA-affected pathways, allowing to achieve overall better long-term response and success.

Official Title
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A Multi-center, Randomized Study on Oral 8-methoxypsoralen Plus UVA With or Without Maintenance Therapy in Mycosis Fungoides EORTC/ISCL Stage IA to IIB

Conditions
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Patch/Plaque Stage Mycosis Fungoides

Intervention / Treatment
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* Drug: 8-methoxypsoralen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histopathologically documented MF clinical stage IA-IIB (see Table1) confirmed by current or previous diagnostic lesion biopsy A Karnofsky performance score > 60 No previous PUVA treatment Anti-ds-DNA (antinuclear antibodies) or anti-Ro/La antibodies: negative Acceptable organ function defined as follows: SGOT (AST) and SGPT (ALT) < 2.5 times the upper limit of normal for the institution Creatinine < 2 times the upper limit of normal for the institution No evidence of severe cardiac insufficiency (NYHA grade III-IV) Women of child bearing potential must have a negative serum pregnancy test (ß-HCG) within seven (7) days prior to randomization Absence of any serious intercurrent illness or infection at time of entry into the study that could interfere with planned treatment Patients must be willing to accept limiting sun exposure on the day receiving PUVA treatment Written informed consent Exclusion Criteria: Pregnancy and Lactation Photosensitive diseases such as lupus erythematosus or basal cell nevus syndrome Skin cancer syndromes such as xeroderma pigmentosum or basal cell nevus syndrome

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 82 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: PUVA maintenance treatment<br>Psoralen plus UVA (PUVA) treatment. The patients receive a standardized dose of oral 8-methoxypsoralen (Oxsoralen) 1 hour before UVA exposure | Drug: 8-methoxypsoralen<br>* 8-methoxypsoralen 10mg per 20 kg body weight 1 hour before UVA exposure<br>* Other names: Oxsoralen®; Gerot Pharmazeutika GmbH, Vienna, Austria;|
| No Intervention: No maintenance treatment<br>observation | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence after complete remission within 12 months post therapy | Recurrence is defined as mSWAT (modified severity weighted assessment tool ) >0. The primary outcome will be evaluated by survival analysis (log-rank test; Kaplan-Meier) comparing time to recurrence after complete remission between patients treated with maintenance therapy vs. patients without maintenance therapy. | 12 months after end of therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quality of life | Compared to baseline | Week -4 to 0; week 12, 24, 36, and 48; month 15, 18, 21, 24, 36, 48, 60, and 72 | 
| HADS | Hospital anxiety depression score, compared to baseline; | Week -4 to 0; week 12, 24, 36, and 48; month 15, 18, 21, 24, 36, 48, 60, and 72 | 
| Cytokine response in serum | Compared to baseline | Week -4 to 0; week 6, 12, 24, and 48 | 
| Levels of regulatory T cells | Compared to baseline | Week -4 to 0; week 6, 12, 24, and 48 | 
| Function of regulatory T cells | Compared to baseline | Week -4 to 0; week 6, 12, 24, and 48 | 
| Microscopic alterations | Quantification of histologic response in skin biopsy | Week -4 to 0; and week 6; optional at week 12, 24, and 48; and in the follow-up from year 1 to 5 | 
| Cytokine expression in the skin | Rt-PCR and immunohistochemical staining investigations | Week -4 to 0; and week 6; optional at week 12, 24, and 48; and in the follow-up from year 1 to 5 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mycosis fungoides, Psoralen and UVA (PUVA), Photochemotherapy, Maintenance treatment, Immune function