The First-in-Human Study of the Hydrogen Sulfate (Hyd-Sulfate) Capsule of the MEK1/2 Inhibitor AZD6244 (ARRY-142886): A Phase I Open-Label Multicenter Trial in Patients with Advanced Cancer

Abstract

Purpose: In part A, the aim was to define the maximum tolerated dose (MTD) of the hydrogen sulfate (Hyd-Sulfate) oral capsule formulation of the mitogen-activated protein kinase kinase inhibitor AZD6244 (ARRY-142886). In part B, the aim was to compare the pharmacokinetic profile of the new Hyd-Sulfate capsule with the initial AZD6244 free-base suspension and further characterize the pharmacodynamic profile and efficacy of the new formulation.Experimental Design: In part A, 30 patients received escalating doses of AZD6244 Hyd-Sulfate twice daily. In part B, 29 patients were randomized to a single dose of the Hyd-Sulfate capsule or free-base suspension, followed by a washout, then a single dose of the alternative formulation. Patients received the Hyd-Sulfate capsule twice daily at MTD of part A thereafter.Results: The MTD of the Hyd-Sulfate capsule was 75 mg twice daily. Dose limiting toxicities were Common Terminology Criteria for Adverse Events grade 3 acneiform rash and pleural effusion. Fatigue (65.7%) and acneiform dermatitis (60.0%) were the most frequent adverse events at the MTD. Based on area under curve 0-24 , exposure of the 75 mg Hyd-Sulfate capsule relative to the 100 mg free-base suspension was 197% (90% confidence interval, 161-242%). Pharmacodynamic analysis showed that inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced extracellular signal-regulated kinase phosphorylation in peripheral blood lymphocytes was related to plasma concentrations of AZD6244, with an estimated IC 50 of 352 ng/ mL and maximum inhibition (E max ) of ∼91%, showing target inhibition. A patient with metastatic melanoma bearing a V600E BRAF mutation achieved a complete response persisting after 15 months of therapy.Conclusions: The AZD6244 Hyd-Sulfate capsule formulation has shown a favorable toxicity, pharmacokinetic, and pharmacodynamic profile, and is being taken forward in ongoing clinical trials. Clin Cancer Res; 16(5); 1613-23. ©2010 AACR.The Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway is a key signaling cascade involved in the regulation of cell cycle, proliferation, differentiation, and survival.Dysregulation of this pathway as a result of aberrant upstream growth factor receptor signaling (1), or by activating mutations in signaling molecules such as Ras and Raf themselves, has been implicated in tumor formation (2).MEK1/2 are central components of the Ras/Raf/MEK/ ERK pathway. They lie downstream of Ras and Raf and are attractive anticancer targets because inhibition of MEK1/2 can potentially block inappropriate signal transduction, originating from the cell surface or due to Ras/ Raf mutations (1-4).AZD6244 is a potent, selective, allosteric inhibitor of MEK1/2 that has shown activity in a number of cell-based growth assays and a variety of human tumor mouse xenograft models, including non-small cell lung cancer (NSCLC) and melanoma (5-7). The clinical efficacy of an oral free-base suspension of AZD6244 has been shown in a phase I trial in...

The novel anti-MEK small molecule AZD6244 induces BIM-dependent and AKT-independent apoptosis in diffuse large B-cell lymphoma

“…10,14,[18][19][20][21][22][23] AZD6244 is a benzimidazole and selective 2nd generation MEK inhibitor with reported activity at nanomolar concentrations against purified MEK1 enzyme in preclinical solid tumor studies. [18][19][20][21][22][23] Further, AZD6244 is a noncompetitive MEK inhibitor with preclinical antitumor activity in solid tumor models including hepatocellular, colon, myeloma, thyroid, pancreatic, melanoma, and breast cancers 19,20,41 and tested clinically in phase 1 24 and phase 2 trials of advanced, refractory colorectal, melanoma, and lung cancer. [25][26][27] AZD6244 has been examined in leukemia and myeloma models, [42][43][44] however to our knowledge, has never been tested in lymphoma.…”

“…[18][19][20][21][22][23] Furthermore, phase 1 and phase 2 solid tumor clinical trials have shown this agent to be well-tolerated and have encouraging clinical efficacy. [24][25][26][27] To our knowledge, minimal data are available on newer generation MEK inhibitors in lymphoma and moreover, this anti-MEK agent has never been examined in lymphoma. We sought to examine the mechanisms of action and cytotoxic effect of the novel 2nd generation MEK small molecule antagonist, AZD6244, in lymphoma cell lines, primary cells, and an in vivo human DLBCL xenograft model.…”

Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer

“…3,6 The approach undertaken in this study was facilitated by several developments: the discovery that genetic alterations that constitutively activate MAPK signaling can promote the dedifferentiation of thyroid-cancer cells, 12,29,30 the clinical availability of a selective MEK inhibitor, 17 and the development of iodine-124 PET-CT technology to quantify the uptake of iodine in a lesion. 18 Our results show that inhibition of the MAPK pathway with selumetinib can renew the therapeutic efficacy of radioiodine by enhancing uptake in patients with thyroid cancer that is refractory to radioiodine.…”

“…16 When BRAF activation is switched off genetically or its downstream signaling is inhibited with kinase inhibitors targeting either MAPK kinase (MEK) or BRAF, the tumors regain the ability to trap radioiodine. These preclinical observations provided the rationale for our pilot clinical study, in which patients who were found to have metastases that were refractory to radioiodine were treated with the selective, allosteric MEK 1 and MEK 2 inhibitor selumetinib (AZD6244, ARRY-142886), 17 and changes in iodine uptake were assessed by means of serial iodine-124 positron-emission tomography (PET)-computed tomography (CT). The use of iodine-124 PET-CT rather than traditional whole-body iodine-131 scintigraphy allowed for precise quantification of iodine uptake before and after selumetinib treatment in individual metastatic lesions ("lesional dosimetry") and prediction of the dose of radiation that could be delivered with iodine-131.…”

Novel biomarkers and therapeutic targets for optimizing the therapeutic management of melanomas

“…The trials are now undergoing to determine the long-term effect of PLX4032, alone or in combination with other agents such as MEK inhibitor, on the survival of melanoma patients [121,122] . In regard with this, the clinical responses have also been observed in a phase II study with orally active and highly selective inhibitor of MEK1/2, AZD6244 (ARRY-142886) or temozolomide performed with 200 patients with advanced melanoma harboring B-Raf E600V mutation [123,124] . On the other hand, it has also been reported that the melanoma patients harboring the activating mutations in the KIT receptor exhibited a partial or complete response to imatinib mesylate [33] .…”