Clinical trial NCT01686594: PUVA Maintenance Therapy in Mycosis Fungoides
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Patch/Plaque Stage Mycosis Fungoides
Keywords: Mycosis fungoides
Psoralen and UVA (PUVA)
Photochemotherapy
Maintenance treatment
Immune function
Lead sponsor: Medical University of Graz
Sponsor class: OTHER
First posted: 2012-09-18
Enrollment: 28
Sex: ALL
Minimum age (years): 18
Maximum age (years): 82
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Recurrence after complete remission within 12 months post therapy
timeFrame: 12 months after end of therapy
Secondary outcomes:
measure: Quality of life
timeFrame: Week -4 to 0; week 12, 24, 36, and 48; month 15, 18, 21, 24, 36, 48, 60, and 72
measure: HADS
timeFrame: Week -4 to 0; week 12, 24, 36, and 48; month 15, 18, 21, 24, 36, 48, 60, and 72
measure: Cytokine response in serum
timeFrame: Week -4 to 0; week 6, 12, 24, and 48
measure: Levels of regulatory T cells
timeFrame: Week -4 to 0; week 6, 12, 24, and 48
measure: Function of regulatory T cells
timeFrame: Week -4 to 0; week 6, 12, 24, and 48
measure: Microscopic alterations
timeFrame: Week -4 to 0; and week 6; optional at week 12, 24, and 48; and in the follow-up from year 1 to 5
measure: Cytokine expression in the skin
timeFrame: Week -4 to 0; and week 6; optional at week 12, 24, and 48; and in the follow-up from year 1 to 5
Other outcomes:
Locations:
city: Graz
country: Austria
facility: Medical University of Graz
city: Innsbruck
country: Austria
facility: Department of Dermatology, Medical University of Innsbruck
city: Linz
country: Austria
facility: Department of Dermatology, General Hospital of the City of Linz
city: Salzburg
country: Austria
facility: Department of Dermatology, Hospital Salzburg - Paracelsus Private Medical University
city: St. Pölten
country: Austria
facility: Department of Dermatology, County Hospital St. Pölten
city: Vienna
country: Austria
facility: Department of Dermatology, Medical University of Vienna
city: Vienna
country: Austria
facility: Department of Dermatology, Hospital Hietzing
city: Wels
country: Austria
facility: Department of Dermatology, Klinikum Wels
city: Wiener Neustadt
country: Austria
facility: Department of Dermatology, County Hospital Wiener Neustadt
Study officials:
affiliation: Medical University of Graz
name: Peter Wolf, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Graier T, Fink-Puches R, Porkert S, Lang R, Pochlauer S, Ratzinger G, Tanew A, Selhofer S, Sator PG, Hofer A, Gruber-Wackernagel A, Legat FJ, Vieyra-Garcia PA, Quehenberger F, Wolf P. Quality of Life, Anxiety, and Depression in Patients With Early-Stage Mycosis Fungoides and the Effect of Oral Psoralen Plus UV-A (PUVA) Photochemotherapy on it. Front Med (Lausanne). 2020 Aug 5;7:330. doi: 10.3389/fmed.2020.00330. eCollection 2020.
citation: Vieyra-Garcia P, Fink-Puches R, Porkert S, Lang R, Pochlauer S, Ratzinger G, Tanew A, Selhofer S, Paul-Gunther S, Hofer A, Gruber-Wackernagel A, Legat F, Patra V, Quehenberger F, Cerroni L, Clark R, Wolf P. Evaluation of Low-Dose, Low-Frequency Oral Psoralen-UV-A Treatment With or Without Maintenance on Early-Stage Mycosis Fungoides: A Randomized Clinical Trial. JAMA Dermatol. 2019 May 1;155(5):538-547. doi: 10.1001/jamadermatol.2018.5905.