Evaluating Safety & Efficacy of Apremilast in the Treatment of Cutaneous Disease in Patients With Recalcitrant Dermatomyositis

Evaluating Safety & Efficacy of Apremilast in the Treatment of Cutaneous Disease in Patients With Recalcitrant Dermatomyositis

A Phase 2, Open Label Single Arm Study for Evaluating Safety & Efficacy of Apremilast in the Treatment of Cutaneous Disease in Patients With Recalcitrant Dermatomyositis

With limited treatment options available for dermatomyositis, the investigators hypothesize that apremilast, a phosphodiesterase-4 (PDE-4) inhibitor, is a safe and efficacious add-on treatment in patients with refractory cutaneous dermatomyositis. The study will investigate the efficacy, safety and toxicity of apremilast given at 30 mg twice daily to patients with refractory cutaneous dermatomyositis. Clinical response will be assessed at 1 and 3 months. Patients will also be evaluated for durability of their response for up to 6 months. Treatment will be monitored with frequent clinical visits (0, 1, 3 and 6 months) and blood tests (CBC, CMP, creatine kinase, aldolase). Treatment will be discontinued at disease progression or unacceptable adverse events. Disease progression is defined as 4 points increase in the cutaneous dermatomyositis disease area and severity index (CDASI) score, worsening of muscle disease by manual muscle testing (MMT-8) score and 5 points increase in dermatomyositis life quality index (DLQI). 5 mm skin biopsies from lesional skin will be performed before treatment with apremilast and after 3 months of treatment for gene expression profiling and confirmatory immunohistochemical stains.

Sponsor Name (PI): Carole Bitar, MD Sub-PI: Erin Boh, MD, PhD; Brittany Stumpf, MD; Collaborator: Nakhle Saba, MD # of Participants Sites: 1, Tulane University 4: Participant Countries: United States II. PRODUCT INFORMATION Study Title: A phase 2, open label single arm study for evaluating safety & efficacy of apremilast in the treatment of cutaneous disease in patients with recalcitrant dermatomyositis. Clinical Phase: Phase II clinical trial Primary Celgene Product: Apremilast III. CONCEPT DESIGN AND RATIONAL Therapeutic Area: Immunology Specialty: Connective tissue disease Disease State: Dermatomyositis 4-If other specify: None 5. Study Rationale: Dermatomyositis is an inflammatory disease that predominantly involves the skin with or without proximal muscle weakness. First line treatment for dermatomyositis is systemic steroids however due to long-term side effects, patients are usually treated with a steroid sparing agent. There is no known consensus on treatment guidelines for dermatomyositis and many anti- inflammatory medications have been successfully used. Tulane University is a referral center for recalcitrant dermatomyositis cases.The investigators present the case of a 57 y.o female patient with multidrug recalcitrant dermatomyositis showing complete remission of her skin disease with apremilast and improvement of her muscle disease. This patient was diagnosed with dermatomyositis. Over a 6-year period, she was treated with adequate trials of multiple immunosuppressive agents, including hydroxychloroquine, mycophenolate mofetil, azathioprine, methotrexate, soriatane, Intravenous immunoglobulin (IVIG), tacrolimus, chlorambucil, infliximab and rituximab. For the last four years, physicians were unable to lower corticosteroids below 40 mg per day. Her disease continued to flare despite these therapies. Chronic steroid use resulted in insulin dependent diabetes mellitus as well as other steroids associated side effects. While on stable doses of mycophenolate mofetil, prednisone and rituximab, the patient developed arthritis and was started on apremilast 30 mg twice a day. Two months into her treatment she noticed significant improvement of her skin disease and then nearly complete clearance of the skin. Her muscle weakness lagged behind and she noticed improvement after 9 months of being on apremilast with normalization of her aldolase and CK. The patient was able to wean off all immunosuppressive agents and prednisone. She was in remission for over 2 years and off all medications. She experienced a mild flare of skin disease recently and she resumed apremilast only and cleared immediately and continues on apremilast as a monotherapy. Patient experienced mild nausea and diarrhea with apremilast that improved four weeks into the treatment. She was able to discontinue insulin, lose weight and she has continued to be clear of both skin and muscle symptoms for over 1.5 years. This case was accepted as a poster presentation at the 2018 Annual Meeting of the American Academy of Dermatology "Poster #: 6672 - Apremilast: a Potential Treatment for Dermatomyositis." Following this successful outcome, the investigators initiated apremilast in 3 other patients with recalcitrant dermatomyositis. Two patients had recalcitrant cutaneous disease and responded to add on therapy of apremilast in 2 months with significant improvement of their skin disease. The third patient had refractory dermatomyositis to several steroid-sparing agents and with severe muscle disease was started on apremilast for arthritis. She experienced significant improvement of her muscle weakness together with decrease in her muscle enzyme creatine kinase. These very exciting findings triggered the idea of studying apremilast as an adjunct treatment for recalcitrant cutaneous disease in dermatomyositis patients. This is a novel idea; apremilast was never studied for dermatomyositis. Apremilast may have more advantages in dermatomyositis compared to other immunosuppressive treatments. Dermatomyositis patients may have lung involvement, and apremilast is an agent that doesn't have lung side effects in contrast to methotrexate for example which is one of the main steroid sparing agents used for dermatomyositis. The pathogenesis of dermatomyositis is multifactorial with environmental, genetic and immune factors contribution.T helper-1 (Th1) and T helper-2 (Th2) immune pathways play a fundamental role in dermatomyositis.There is increase in proinflammatory cytokines including tumor necrosis factor alpha (TNF-α), interleukin (IL) 1, IL 6, and interferon (INF) α,γ shifting the immune balance to a Th1 response.Th1 immune response was also involved in the pathogenesis of interstitial pneumonia in the setting of dermatomyositis.IL4 released by lymphocytes infiltrating skin and muscles in dermatomyositis patients contributes to increase in Th2 response in conjunction with Th1 response. Apremilast is a PD4-E inhibitor currently used for psoriasis and psoriatic arthritis.However, its usage on patients with dermatomyositis has not been investigated. By inhibiting PDE-4 apremilast increases the level of cyclic adenosine monophosphate (c-AMP), leading to decreased expression of proinflammatory cytokines including TNF-α and INF-γ thus inhibiting Th1 response. Apremilast can also block Th2 response by interfering with the level of IL6 secreted by type2 macrophages.While the mechanism of action of apremilast in dermatomyositis is unknown, we suggest that apremilast can be a potential treatment option for dermatomyositis through interfering with Th1 and Th2 response. Apremilast is a well-tolerated oral medicine with transient gastrointestinal side effects. Apremilast offers an additional treatment option for those patients with recalcitrant dermatomyositis, unresponsive to more conventional therapy. 6. Treatment and Dosing: Investigators will enroll patients seen at our facilities with a known diagnosis of dermatomyositis who are still experiencing cutaneous disease after a trial of systemic steroids and one steroid-sparing agent. Investigators will add apremilast to their treatment regimen according to the approved dosage for psoriasis and psoriatic arthritis: 10 mg orally one time on day 1, 10 mg orally twice daily on day 2, 10 mg orally in AM and 20 mg orally in PM on day 3, 20 mg orally twice daily on day 4, 20 mg orally in AM and 30 mg orally in PM on day 5, then 30 mg orally twice daily thereafter. 7. Brief Study Synopsis: With limited treatment options available for dermatomyositis, investigators hypothesize that apremilast, a phosphodiesterase-4 (PDE-4) inhibitor, is a safe and efficacious add-on treatment in patients with recalcitrant cutaneous dermatomyositis. The study will investigate the efficacy, safety and toxicity of apremilast given at 30 mg twice daily to patients with recalcitrant cutaneous dermatomyositis. Clinical response will be assessed at 1 and 3 months. Patients will also be evaluated for durability of their response for up to 6 months. Treatment will be monitored with frequent clinical visits (0, 1, 3 and 6 months) and blood tests (CBC, CMP, CK, aldolase). Treatment will be discontinued at disease progression or unacceptable adverse events. Disease progression is defined as a 4 points increase in CDASI score, worsening of muscle disease by MMT-8 score and 5 points increase in DLQI. 5 mm skin biopsies from lesional skin will be performed before treatment with apremilast and after 3 months of treatment for gene expression profiling and confirmatory immunohistochemical stains. 8. Sampling and correlative analysis Although, the proposed mechanism of action of apremilast is though PDE-4 inhibition resulting in c-AMP upregulation, the exact biological process that leads to dermatological response in dermatomyositis remains ill-defined.Investigators propose to perform gene expression profiling (GEP) using RNA sequencing on skin biopsies collected before and after treatment with apremilast. In addition, we plan to confirm our GEP findings at the protein level using immunohistochemical (IHC) stains. A. Tissue sampling and preparation Tissue collection 5 mm punch biopsy from dermatomyositis skin lesions will be performed at baseline and another 5 mm punch biopsy will be performed at the 3-month time point. Each biopsy will be vertically split in two pieces and snap frozen on dry ice then it will be stored at -80C for further analysis with RNA sequencing and IHC stains. RNA extraction At the end of all timeline collections, each skin biopsy will be mechanically broken down followed by mRNA extraction using the RNeasy extraction Kit from QIAGENzz. mRNA will then be stored at -80°C for subsequent RNA sequencing as detailed below. B. Correlative Analysis Determining the mechanism of action of apremilast in dermatomyositis. Gene expression profiling RNA extracted form skin biopsies collected before and after in vivo treatment with apremilast (as detailed above) will be subjected to RNA sequencing. Illumina strand-specific TruSeq libraries will be prepared from the polyA selected RNA and subjected to 1x100 base sequencing on an Illumina HiSeq2500 machine. The number of samples proposed here (10 samples before treatment and 10 samples after treatment) is expected to yield sufficient statistical power for this approach; smaller numbers have been used in similar approaches to investigate drugs' mechanism of action (usually three samples). RNA-seq analysis will be performed in conjunction with the Tulane Cancer Crusaders Next Generation Sequence Analysis Core (Tulane Cancer Center - https://tulane.edu/som/cancer/research/core-facilities/cancer-crusaders/). Gene and isoform expression will be determined using RSEM and differential expression will be analyzed using EB-seq. Genes that are identified as differentially expressed between the two groups with a False Discovery Rate (FDR) of < 0.05 will be subjected to analysis by Ingenuity (IPA, Redwood City, CA). This analysis will group the identified genes into specific pathways, cell types, or disease process. A similar approach will be conducted using Gene Set Enrichment Analysis (GSEA). These experiments and GEP analysis will be performed in conjunction with our collaborator's (Dr. Nakhle Saba) lab, given his extensive experience in this field. Protein analysis Information identified by Ingenuity or GSEA (signaling pathways, regulatory molecules, etc…) will be verified using IHC staining on select samples.

Patients with refractory cutaneous dermatomyositis will be started on apremilast 30 mg twice a day in addition to a stable dose of their treatment regimen (including steroids and steroid sparing agents).

The Primary Endpoint Analysis Would be Overall Response Rate Measured by the Number of Participants Experiencing at Least 4 Points Decrease in CDASI Activity Score at 3 Months.

Cutaneous dermatomyositis disease area and severity index (CDASI) activity score is a validated tool to measure skin disease activity in dermatomyositis. The overall response rate (ORR) includes partial and complete responses. Complete response is defined by a CDASI activity score of zero. Partial response is defined by a decrease of CDASI activity score of at least 4 points. Calculation is performed as the CDASI activity score at 3 month(s) minus the score at baseline. Missing data will be handled using the last observation carried forward approach (LOCF). CDASI activity score: Units on a scale from 0-100. Higher scores represent worse outcome.

2. The Secondary Endpoint Analysis Would be Safety as Measured by the Number of Participants Experiencing Adverse Events and Serious Adverse Events Occurring During 6 Months of Therapy and 1 Month Follow up.

The proportion of participants experiencing adverse events and serious adverse events was measured over 7 months period (6 months during the study and 1 month follow up) using Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Grade refers to severity of the AE. The CTCAE displays Grades 1 to 5 with unique clinical descriptions of severity for each AE: Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age- appropriate instrumental Activity of Daily Living (ADL) Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL Grade 4 Life-threatening consequences; urgent intervention indicated Grade 5 Death related to AE All adverse events subjects experienced were grade 1 or 2 which is mild to moderate in severity.

An Additional Secondary Endpoint Analysis Would be Durability of Response Measured Participants CDASI Activity Score or Change in Their CDASI Activity Score at 6 Months Compared to 3 Months.

The durability of response will be measured using the CDASI activity score at 6 months minus CDASI activity score at 3 months. Complete response durability is defined as zero or minus difference between CDASI activity score at 6 months and CDASI activity score at 3 months. Partial response durability is defined as >4 points difference between CDASI activity score at 6 months and CDASI activity score at 3 months. Missing data will be handled using the last observation carried forward approach (LOCF). CDASI activity score: Units on a scale from 0-100. Higher scores represent worse outcome.

An Additional Secondary Endpoint Analysis Would Assess Quality of Life as Measured at 3 Months Compared to Quality of Life Measured at 6 Months

Dermatology Life Quality Index (DLQI) is a validated tool to measure quality of life in patients with skin disease. Complete response is defined by a DLQI of zero at 3, and 6 months. Partial response is defined by a decrease of DLQI of at least 5 points at 3, and 6 months compared to baseline. Calculation is performed as the DLQI at 3, and 6 months minus the score at baseline. Missing data will be handled using the last observation carried forward approach (LOCF). Units : Units on a scale from 0-30, higher scores represent worse outcome.

An Additional Endpoint Analysis Would Assess the MMT-8 Score in Patients With Muscle Disease as Measured at 3 and 6 Months Compared to Baseline.

MMT-8 (Manual Muscle Testing-8) score is a validated tool to assess muscle strength. Calculate the mean change in MMT-8 score at 3 and 6 month(s) compared to baseline in patients with muscle disease. Units: Units on a scale. Scale goes from 0-150. 150 is perfect strength.

An Additional Endpoint is to Assess the Gene Expression Profiling and Immunohistochemistry Analysis Change on Skin Biopsies at 3 Months Compared to Baseline.

Skin biopsies from lesional skin will be performed before treatment with apremilast and after 3 months of treatment to assess changes in gene expression profiling and immunohistochemistry stain. Gene expression profiling will be analyzed using inferential statistics with a False Discovery Rate (FDR) of < 0.05.

An Additional Endpoint is to Assess the Immunohistochemistry Analysis Change on Skin Biopsies at 3 Months Compared to Baseline.

Skin biopsies from lesional skin will be performed before treatment with apremilast and after 3 months of treatment to assess changes in immunohistochemistry stain.

Inclusion Criteria: Must understand the risks and the benefits/purpose of the study and provide signed and dated informed consent. Must be 18 years at time of signing the informed consent form. Willing to participate in all required evaluations and procedures in the study including the ability to swallow pills without difficulty. Patients must have a diagnosis of DM based upon the characteristic cutaneous findings proposed by Sontheimer[6] and/or a skin biopsy consistent with DM. Patients must be candidate for systemic therapy for their DM skin disease defined by inadequate response to aggressive sun protection along with the use of potent topical corticosteroids and/or immunomodulators. Patients with a diagnosis of dermatomyositis on steroid-sparing agent and/or systemic steroids (maximum dose of prednisone 1mg/Kg) and still having cutaneous disease activity of at least 5 on the CDASI scale. If on immunosuppressive treatments and/or steroids, patients must be on stable doses for at least 4 weeks (28 days). Patients must undergo age appropriate cancer screening. Females of childbearing potential (FCBP) must have a negative pregnancy test at screening (day 0 of the study and every month throughout the study). While on investigational product and for at least 28 days after taking the last dose of investigational product. Exclusion Criteria: Increasing or changing dose of topical therapy within 14 days of study day 0 (including but not limited to topical corticosteroids, tacrolimus, pimecrolimus). Increasing or changing systemic steroids dosing within 28 days of study day 0. Increasing or changing dosing for concurrent therapy agents within 28 days or 5 half-lives of the biologic agent, whichever is longer, before study day 0: methotrexate, azathioprine, mycophenolate mofetil, hydroxychloroquine, dapsone, leflunomide, cyclosporine, biologic agents (anti-TNFs), IVIG, rituximab. History of any clinically significant (as determined by the investigators) cardiac, endocrinologic, pulmonary, neurologic, psychiatric, hepatic, renal, hematologic, immunologic, or other major uncontrolled disease. Any condition, including the presence of laboratory abnormalities, which places the patient at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study. Pregnant or breastfeeding. Untreated Latent Mycobacterium tuberculosis infection or active tuberculosis infection as indicated by a positive Purified Protein Derivative (PPD) skin test or T-spot. Any condition, including the presence of laboratory abnormalities that places the patient at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study. Patients with acute dermatomyositis onset and rapid progression of muscle disease or significant systemic involvement including pulmonary diseases associated with DM. Prior major surgery or major life-threatening medical illness within 2 weeks. Inflammatory bowel disease, malabsorption or any other gastrointestinal motility disorders that limit the absorption of the study drug. Active hepatitis B or C infection with detectible viral nucleic acid in the blood or known Human Immunodeficiency Virus (HIV) positivity. Prior history of suicide attempt at any time in the patient's lifetime prior to screening or randomization, or major psychiatric illness requiring hospitalization within the last 3 years. Active substance abuse or a history of substance abuse within 6 months prior to screening. Use of any investigational drug within 4 weeks prior to randomization, or 5 pharmacokinetic/pharmacodynamic half-lives, if known (whichever is longer). Prior treatment with apremilast. Any severe systemic illness requiring IV antibiotics within the two weeks prior to initiation of the study drug. Malignancy or history of malignancy within the past four years, except for: treated [ie, cured] basal cell or squamous cell in situ skin carcinomas; treated [ie, cured] cervical intraepithelial neoplasia (CIN) or carcinoma in situ of cervix with no evidence of recurrence within the previous 4 years.

Data and research resources generated by this study will be made available to the research community and to the public at large. This strategy includes, but not limited to, presentations (poster or oral) at local, national, and international meetings; published abstracts, and journal articles (peer reviewed). Contact information will be provided in publications for direct inquiries of researchers. Data generated from sequencing and gene expression profiling will be deposited into the Gene Expression Omnibus (GEO), NCBI, to be accessible by general public. The study protocol will be shared with other researchers on the clinical trial.gov website. No identified personal patient informations will be shared.

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