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P6800Tolerability assessment of treatment areas up to 100 cm2 with ingenolmebutate gel 0.05% in patients with actinic keratosis lesions
Peter Foley, MD, Skin and Cancer Foundation, Carlton, Australia; JanelleKatsamas, LEO Pharma Pty Ltd, Brisbane, Australia; Michael Jarret, MD,DermResearch Inc, Austin, TX, TX, United States; Peter Welburn, PhD, LEOPharma Pty Ltd, Brisbane, Australia
We present 2 clinical studies suggesting an acceptable safety profile of treatmentareas up to 100 cm2with ingenol mebutate gel 0.05% patients with actinic keratosis.The initial phase I, multicenter, open-label study (PEP005-022) was designed tostudy the safety and tolerability of ingenol mebutate gel 0.05%, once daily for 2consecutive days (days 1 and 2) in the treatment of AKs on the dorsal forearm (s) intreatment areas of from 25 to 100 cm2. Patients N ¼ 63, all male per inclusioncriteria, with a mean age of 68.1 years (range, 44-85) were assigned to 8 cohorts withescalating treatment area size. Follow-up visits for safety assessments were made ondays 2, 3, 8, 15, 29, and 57. No increase in treatment-related AEswas observedwhencomparing the 25, 50, 75 or 100 cm2 treatment areas. All patients with a treatmentarea of 100 cm2 tolerated 2 doses and this area was concluded to be safe for thesubsequent pharmacokinetic (PK) study (PEP005-017). Following from the firststudy a phase II, double-blind, vehicle-controlled study (PEP005-017) was designedto evaluate the potential systemic exposure of ingenol mebutate. Patients receivedingenol mebutate gel 0.05% (N¼ 13, 6male 7 femalemean age of 63.3) or vehicle gel(N¼ 3 female, mean age 64.7) once daily for 2 consecutive days to a contiguous 100cm2 treatment area on the dorsal forearm with multiple AK lesions. Blood sampleswere collected for pharmacokinetic analysis predose on day 1, predose on day 2 and30 minutes and 1, 2, 4, 8, 12, and 24 hours following the day 2 dose application.Whole blood samples from all 16 patients were quantified for ingenol mebutate andits two primarymetabolites. No detectable (lower limit of quantitation [LLOQ]¼ 0.1ng/mL) systemic exposure of ingenol mebutate, PEP015, and PEP025 were detectedin any samples. Safety and efficacy were assessed on days 2, 3, 8, 15, 29, and 57. Inpatients treated with ingenol mebutate gel 0.05%, the mean composite local skinresponse (LSR) score peaked at day 3, with a score of 6.6 (theoretical maximum ofthe scale is 24), and returned to pretreatment levels by day 57. The highestcomposite LSR score reported in the study was 12. The evidence presented herefurther supports an acceptable topical safety profile up to what represents astandard anatomical unit (100 cm2).
APRIL 20
nsored by Peplin Operations Pty Ltd.
100% spoP6097Topical treatment of murine squamous cell carcinoma with ingenolmebutate gel 0.25%
Sarah-Jane Cozzi, PhD, Sarah-Jane Cozzi, Brisbane, Australia; Andreas Suhrbier,PhD, Queensland Institute of Medical Research, Herston, QLD, Australia; CiniJames, University of Queensland Diamantina Institute, Woolloongabba, QLD,Australia; Steven Ogbourne, PhD, University of the sunshine coast,Maroochydore DC QLD, Australia; Thuy Le, Queensland Institute of MedicalResearch, Herston, QLD, Australia
Actinic keratosis (AK) can develop into squamous cell carcinoma (SCC) and ingenolmebutate gel 0.015% and 0.05% is approved in the US by FDA as a topical treatmentfor AK. The aim of this studywas to assess the efficacy of ingenol mebutate gel 0.25%(IngMeb) as a short course topical treatment for SCC inoculated in mice and to gaininsights into the mechanism of action. Wild-type, immunocompetent SKH1/hr miceand the syngeneic UV-induced mouse SCC cell line, T7 were used in this study. T7cells were injected shallow subcutaneously in female SKH1 mice and tumors wereallowed to develop over 4 days. Established tumorswere treated topically, once dailyfor 2 days with IngMeb or placebo gel. Tumor growth was monitored over time andmice were sacrificed if tumors reached an area of 100 mm2. Histology andtransmission electron microscopy (EM) of treated tumors were undertaken todetermine the mechanism of action. Treatment of T7 tumors with IngMeb resultedin a significant reduction in the number of mice with tumors reaching 100mm2 (log-rank test placebo vs IngMeb; P ¼ .0009), with 70% of mice treated with IngMeb gelshowing no signs of tumor reoccurrence 4 months after treatment, suggesting thatcomplete cure was achieved; no cure was evident with placebo gel. Histologicexamination showed that IngMeb treatment resulted in acute localized inflamma-tion, recruitment of neutrophils, hemorrhage and crusting, which resolved overseveral weeks. EM revealed swelling of cancer cell mitochondria within 1 hour, withdisruption of the inner mitochondrial membranes evident at 6 hours posttreatmentwith IngMeb. Changes to the nucleus were also evident after treatment withIngMeb. The following observations were made posttreatment with IngMeb: 6hours after chromatin within tumor cells appeared to aggregate, 16 hours after thenuclear envelope appeared to be disrupted and by 24 hours after in some tumor cellsno nuclear envelope could be detected, with chromatin appearing to be leaking intothe cytosol. In addition, primary necrosis of cancer cells was clearly evident by 24hours. ELISA specific for T7 SCC antibodies in serum showed increased titresfollowing IngMeb treatment. This study reports the successful treatment of SCCtumors in an immunocompetent mouse with IngMeb gel 0.25%, and supports theview that IngMeb induces primary necrosis and activates the immune system.
earch study consumables were sponsored by Peplin Ltd.
100% res13
P6831Treating squamous cell carcinomas with intralesional 5-fluorouracil: Casereport of patient with multiple squamous cell carcinomas in the setting ofvemurafenib treatment for melanoma
Virginia Alldredge, Tulane University School of Medicine, New Orleans, LA,United States; David DeVries, MD, Central Dermatology Center, Chapel Hill, NC,United States; Nancy E. Thomas, MD, PhD, University of North Carolina at ChapelHill, Chapel Hill, NC, United States
Background: Since gaining FDA approval in August 2011, vemurafenib has become adrug of choice in the treatment of patients with BRAF mutant metastatic melanoma.While vemurafenib inhibits RAF activation in BRAFmutant melanoma cells, the drugactivates the same pathway in BRAF wild type cells. This activation is believed tohave a causative relationship to the development of cutaneous squamous cellcarcinoma (cSCC) and keratoacanthoma (KA) in patients receiving systemic therapy,specifically when upstream mutations are present in the RAS gene (eg. HRASmutation). As a side effect of therapy with vemurafenib, 15% to 30% of patientsdevelop cSSCs, with some patients developing multiple lesions. Patients with agegreater than 65, previous NMSC, or chronic sun exposure are at increased risk forthis drug side effect. While the standard of care for treatment of cSCC is surgicalexcision, the use of intralesional chemotherapy has been reported as a nonsurgicaloption for cSCC outside the setting of vemurafenib therapy.
Case report: We present the case of an 83-year-old woman with stage IIIB metastaticmelanomawho presented on day 36 of systemic vemurafenib therapy (720mg orallytwice daily) with multiple hyperkeratotic red papules. Drug was held for 12 daysthen restarted at 480 mg twice daily. Eight biopsies were obtained; 7 of which wereconsistent with well-differentiated cSCC. Four biopsy-proven cSCCs were treatedwith surgical excision. As an alternative to further surgical management, with thegoal of reducing patient morbidity, intralesional 5-flurouracil was used for manage-ment of remaining biopsy proven cSCCs. In addition, 29 clinically suspected SCCswere treated presumptively over a 5-month period. Patient received weeklyintralesional injections of 0.05-0.5 cc 5-fluorouracil 50 mg/mL per lesion dependingon size, with up to 13 lesions injected per clinic visit. Lesions were treated weeklyuntil clinical features of cSCC were no longer observed. The number of treatmentsper lesion ranged from 2 to 9. CBC and LFTs were monitored and remained withinnormal limits. We believe intralesional 5-flurouracil represents a reasonable alter-native to surgery for management of cSCC in the setting of vemurafenib therapy.
cial support: None identified.
CommerP6150Umbilical basal cell carcinoma: An unusual location
Stella Ramos-e-Silva, Universidade Federal do Rio de Janeiro, Rio de Janeiro,Brazil; Juliana Marques, Universidade Federal do Rio de Janeiro, Rio de Janeiro,Brazil; Marcia Ramos-e-Silva, Universidade Federal do Rio de Janeiro, Rio deJaneiro, Brazil; Taissa Canedo, Universidade Federal do Rio de Janeiro, Rio deJaneiro, Brazil; Tullia Cuzzi, Universidade Federal do Rio de Janeiro, Rio deJaneiro, Brazil
Background: Basal cell carcinoma (BCC) is a slow growing malignant epidermaltumor that evolves with local invasiveness and rare metastases. It occurs mostly intropical countries and as patients’ age increases. It is the most frequent cutaneousmalignancy accounting for 70% to 80% of all skin cancers. Its most importantcausative factor is ultraviolet radiation exposure thus themajority is observed on sunexposed skin; nearly 85% occurring on head and neck. It may also occur on any otherskin surface, including umbilicus, to which this report refers.
Case report: A 75-year-old woman complained of a pearled and ulcerated erythem-atous papule, which had been present for approximately one year inside her navel.She had no previous history of skin cancer, exposure to radiation or arsenic, surgery,trauma, or of any preexisting disease on the abdominal region. Dermatoscopicexamination presented evidence of arborising vessels, enhancing the suspicion ofBCC. After surgical removal of the lesion, histologic examination confirmed initialBCC diagnosis.
Discussion: Despite BCC being common skin tumor, umbilicus is a very unusuallocation and has only been reported seven times to date. Among the differentialdiagnosis are umbilical endometriosis and squamous cell carcinoma. Treatmentoptions include the following interventions: cryosurgery, curettage and electro-dessication, 5-fluorouracil, 5% imiquimod cream, photodynamic therapy, andsurgery (conventional or Mohs micrographic surgery). Our patient was submittedto conventional surgery with a very good result.
cial support: None identified.
CommerJ AM ACAD DERMATOL AB167
