MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study.

BACKGROUND: Patients with melanoma harbouring Val600 BRAF mutations benefit from treatment with BRAF inhibitors. However, no targeted treatments exist for patients with BRAF wild-type tumours, including those with NRAS mutations. We aimed to assess the use of MEK162, a small-molecule MEK1/2 inhibitor, in patients with NRAS-mutated or Val600 BRAF-mutated advanced melanoma. METHODS: In our open-label, non-randomised, phase 2 study, we assigned patients with NRAS-mutated or BRAF-mutated advanced melanoma to one of three treatment arms on the basis of mutation status. Patients were enrolled at university hospitals or private cancer centres in Europe and the USA. The three arms were: twice-daily MEK162 45 mg for NRAS-mutated melanoma, twice-daily MEK162 45 mg for BRAF-mutated melanoma, and twice-daily MEK162 60 mg for BRAF-mutated melanoma. Previous treatment with BRAF inhibitors was permitted, but previous MEK inhibitor therapy was not allowed. The primary endpoint was the proportion of patients who had an objective response (ie, a complete response or confirmed partial response). We report data for the 45 mg groups. We assessed clinical activity in all patients who received at least one dose of MEK162 and in patients assessable for response (with two available CT scans). This study is registered with ClinicalTrials.gov, number NCT01320085, and is currently recruiting additional patients with NRAS mutations (based on a protocol amendment). FINDINGS: Between March 31, 2011, and Jan 17, 2012, we enrolled 71 patients who received at least one dose of MEK162 45 mg. By Feb 29, 2012 (data cutoff), median follow-up was 3·3 months (range 0·6-8·7; IQR 2·2-5·0). No patients had a complete response. Six (20%) of 30 patients with NRAS-mutated melanoma had a partial response (three confirmed) as did eight (20%) of 41 patients with BRAF-mutated melanoma (two confirmed). The most frequent adverse events were acneiform dermatitis (18 [60%] patients with NRAS -mutated melanoma and 15 [37%] patients with the BRAF-mutated melanoma), rash (six [20%] and 16 [39%]), peripheral oedema (ten [33%] and 14 [34%]), facial oedema (nine [30%] and seven [17%]), diarrhoea (eight [27%] and 15 [37%]), and creatine phosphokinase increases (11 [37%] and nine [22%]). Increased creatine phosphokinase was the most common grade 3-4 adverse event (seven [23%] and seven [17%]). Four patients had serious adverse events (two per arm), which included diarrhoea, dehydration, acneiform dermatitis, general physical deterioration, irregular heart rate, malaise, and small intestinal perforation. No deaths occurred from treatment-related causes. INTERPRETATION: To our knowledge, MEK162 is the first targeted therapy to show activity in patients with NRAS -mutated melanoma and might offer a new option for a cancer with few effective treatments. FUNDING: Novartis Pharmaceuticals.

Effects of Auron-Misheil-Therapy in human in vitro skin models.

Auron-Misheil-Therapy (AMT) is currently under development as an anticancer treatment. The aim of the present study was the identification of possible effects and properties of AMT with regard to human skin. The study consisted of three experimental phases. Phase 1 assessed the effects of AMT on the viability of 2-D evaluated and accredited cell cultures of three cell types of human skin, namely: keratinocytes, melanocytes and fibroblasts. Three separate assays were used in this phase. Phase 2 was designed to clarify the effects of AMT on cell viability to investigate the mode of action of AMT. Two possible modes of action were investigated: proliferation inhibition and apoptosis. There was one assay to assess proliferation, and two independent assays to assess apoptosis. The third phase assessed the effects of AMT on two different types of 3-D skin models, an ex vivo model and a de novo reconstituted model. In the phase 1 tests, reduction of cell viability by AMT was demonstrated in all three cell types. In phase 2, the cell proliferation assay showed decreased proliferation rates in the presence of AMT in three out of four cell populations. In phase 3, histochemical investigations with 3-D models indicated that AMT induces desquamation, most likely as the result of apoptosis of epidermal cells. The experiments generally showed that AMT does not harm human skin at concentrations up to 3%.

A pilot study of Auron Misheil Therapy in patients with advanced cervical cancer: tumor response and its correlation with clinical benefit response, and preliminary quality of life data.

This pilot study of Auron Misheil Therapy (AMT) in women with advanced cervical cancer was an open-label, single arm study to collect initial safety, efficacy, and quality of life data. Fifteen women with stage IIIb or IVa cervical cancer were given twice daily intramuscular injections of AMT (insulin, chlorpheniramine and camomile extract) for 3 months. Objective tumor response was evaluated using CT scans and analyzing the data according to the WHO RECIST criteria. Clinical Benefit Response (CBR) was assessed using a composite score comprising Karnovsky performance status, pain intensity and body weight. Safety and tolerability parameters were monitored. Quality of life was evaluated using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC C-30). Eight out of 15 patients were rated as clinical responders (CBR) at 12 weeks. One patient had a partial response and 11 stable disease (WHO RECIST criteria). AMT was well tolerated. An initial analysis showed improvement in quality of life (EORTC C-30). Promising response rates, early indications of improved quality of life, and no significant safety issues mean that the second, randomized phase of the trial can be initiated with a longer treatment duration. Patients with advanced cervical cancer showed positive clinical responses to Auron Misheil Therapy. The treatment was well tolerated, with indications of improved quality of life.

AMT: preclinical pharmacology studies.

Auron-Misheil-Therapy (AMT) consisting of aqueous camomile extract supplemented with calcium, vitamins, the antihistamine chlorpheniramine and human insulin is under development as anti-cancer treatment. AMT was preclinically investigated in tumour cell lines and tumour xenografts to guide clinical phase I/II studies. AMT was tested against 56 human tumour cell lines, in a clonogenic assay in 98 patient-derived xenografts and in in vivo studies. AMT showed in vitro cytotoxic activity with highest susceptibility in cervical cancer, glioblastoma and colon cancers. In the clonogenic assay, anti- cancer activity of AMT was most active in cervical and uterine tumours, in colon cancer, glioblastoma, leukaemia, melanoma and pancreatic cancer. In vivo, AMT showed slight activity in tumour xenograft models of colon and mammary cancer. It also showed immune stimulatory effects by induction of IL-6- and TNF-alpha secretion in human PBMCs. The immune stimulatory potential of AMT, together with slight anti-tumour efficacy observed in the present study, indicates a role of AMT in tumour therapy.