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Chandra Bartholomeusz - One of the best experts on this subject based on the ideXlab platform.

  • MEK inhibitor Selumetinib (AZD6244; ARRY-142886) prevents lung metastasis in a triple-negative breast cancer xenograft model
    Molecular cancer therapeutics, 2015
    Co-Authors: Chandra Bartholomeusz, Paul D. Smith, Ali Dadbin, Hitomi Saso, Kimie Kondo, Jangsoon Lee, Xuemei Xie, Mary Kathryn Pitner, Kevin N. Dalby, Naoto T. Ueno
    Abstract:

    Patients with triple-negative breast cancer (TNBC) have a poor prognosis because TNBC often metastasizes, leading to death. Among patients with TNBC, those with extracellular signal-regulated kinase 2 (ERK2)-overexpressing tumors were at higher risk of death than those with low-ERK2-expressing tumors (hazard ratio, 2.76; 95% confidence interval, 1.19-6.41). The MAPK pathway has been shown to be a marker of breast cancer metastasis, but has not been explored as a potential therapeutic target for preventing TNBC metastasis. Interestingly, when we treated TNBC cells with the allosteric MEK inhibitor Selumetinib, cell viability was not reduced in two-dimensional culture. However, in three-dimensional culture, Selumetinib changed the mesenchymal phenotype of TNBC cells to an epithelial phenotype. Cells that undergo epithelial-mesenchymal transition (EMT) are thought to contribute to the metastatic process. EMT leads to generation of mesenchymal-like breast cancer cells with stem cell-like characteristics and a CD44(+)CD24(-/low) expression pattern. We tested the hypothesis that targeted inhibition of the MAPK pathway by Selumetinib inhibits acquisition of the breast cancer stem cell phenotype and prevents lung metastasis of TNBC. TNBC cells treated with Selumetinib showed inhibition of anchorage-independent growth, an indicator of in vivo tumorigenicity (P < 0.005), and decreases in the CD44(+)CD24(-/low) fraction, ALDH1 activity, and mammosphere-forming efficiency. Mice treated with Selumetinib formed significantly fewer lung metastases than control mice injected with vehicle (P < 0.05). Our data demonstrate that MEK inhibitors can inhibit breast cancer stem cells and may have clinical potential for the prevention of metastasis in certain cases in which tumors are MAPK dependent.

  • Abstract LB-362: The MEK inhibitor Selumetinib (AZD6244 - ARRY-142886) prevents lung metastasis in a triple-negative breast cancer (TNBC) xenograft model
    Experimental and Molecular Therapeutics, 2012
    Co-Authors: Chandra Bartholomeusz, Paul D. Smith, Hitomi Saso, Gabriel N. Hortobagyi, Kimie Kondo, Dadbin Ali, Naoto T. Ueno
    Abstract:

    Patients with TNBC are negative for estrogen receptor, progesterone receptor, and HER2 expression, and have a very poor prognoses because tumors often metastasize, leading to death. Preventing metastasis as well as inhibiting the tumor growth, is crucial to improving the prognosis of TNBC. We previously showed that patients with ERK2-overexpressing TNBC were at higher risk of death than those with low-ERK2-expressing tumors. Interestingly, when we treated the TNBC cells lines MDA-MB-231 and SUM-149 with the MEK1/2 ATP uncompetitive kinase inhibitor (Selumetinib) at concentrations of 0.1 and 1.0 μM, it did not reduce cell viability in a two-dimensional (2D) cell culture. However, in a three-dimensional (3D) cell culture model, Selumetinib changed the mesenchymal phenotype of TNBC to an epithelial phenotype. Cells undergoing epithelial-mesenchymal transition are well known to potentially contribute to the metastatic process and have increased ability to form mammospheres. Thus, we hypothesized that targeted inhibition of the MEK-ERK pathway by Selumetinib may prevent lung metastasis in TNBC. In the present study, we observed that SUM-149 cells treated with Selumetinib (0.1, 1.0 μM) exhibited cell-cycle arrest at G1 but did not exhibit apoptosis indicated by an increased proportion of cells at sub-G1 phase. Both SUM-149 and MDA-MB-231 cells treated with Selumetinib exhibited significant inhibition of anchorage-independent growth, an indicator of in vivo tumorigenicity (P Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-362. doi:1538-7445.AM2012-LB-362

  • mek1 2 inhibitor Selumetinib azd6244 inhibits growth of ovarian clear cell carcinoma in a pea 15 dependent manner in a mouse xenograft model
    Molecular Cancer Therapeutics, 2012
    Co-Authors: Chandra Bartholomeusz, Anna Kazansky, Hitomi Saso, Tetsuro Oishi, Ugur Akar, Ping Liu, Kimie Kondo, Savitri Krishnamurthy, J S Lee
    Abstract:

    Clear cell carcinoma (CCC) of the ovary tends to show resistance to standard chemotherapy, which results in poor survival for patients with CCC. Developing a novel therapeutic strategy is imperative to improve patient prognosis. Epidermal growth factor receptor (EGFR) is frequently expressed in epithelial ovarian cancer. One of the major downstream targets of the EGFR signaling cascade is ERK. PEA-15, a 15-kDa phosphoprotein, can sequester ERK in the cytoplasm. MEK1/2 plays a central role in integrating mitogenic signals into the ERK pathway. We tested the hypothesis that inhibition of the EGFR-ERK pathway suppresses tumorigenicity in CCC, and we investigated the role of PEA-15 in ERK-targeted therapy in CCC. We screened a panel of four CCC cell lines (RMG-I, SMOV-2, OVTOKO, and KOC-7c) and observed that the EGFR tyrosine kinase inhibitor erlotinib inhibited cell proliferation of EGFR-overexpressing CCC cell lines through partial dependence on the MEK/ERK pathway. Further, erlotinib-sensitive cell lines were also sensitive to the MEK inhibitor Selumetinib (AZD6244), which is under clinical development. Knockdown of PEA-15 expression resulted in reversal of Selumetinib-sensitive cells to resistant cells, implying that PEA-15 contributes to Selumetinib sensitivity. Both Selumetinib and erlotinib significantly suppressed tumor growth (P < 0.0001) in a CCC xenograft model. However, Selumetinib was better tolerated; erlotinib-treated mice exhibited significant toxic effects (marked weight loss, severe skin peeling) at high doses. Our findings indicate that the MEK/ERK pathway is a potential target for EGFR-overexpressing CCC and indicate that Selumetinib and erlotinib are worth exploring as therapeutic agents for CCC.

  • MEK1/2 Inhibitor Selumetinib (AZD6244) Inhibits Growth of Ovarian Clear Cell Carcinoma in a PEA-15-dependent Manner in a Mouse Xenograft Model
    Molecular cancer therapeutics, 2011
    Co-Authors: Chandra Bartholomeusz, Anna Kazansky, Hitomi Saso, Tetsuro Oishi, Ugur Akar, Ping Liu, Kimie Kondo, Savitri Krishnamurthy, Jangsoon Lee, Francisco J. Esteva
    Abstract:

    Clear cell carcinoma (CCC) of the ovary tends to show resistance to standard chemotherapy, which results in poor survival for patients with CCC. Developing a novel therapeutic strategy is imperative to improve patient prognosis. Epidermal growth factor receptor (EGFR) is frequently expressed in epithelial ovarian cancer. One of the major downstream targets of the EGFR signaling cascade is ERK. PEA-15, a 15-kDa phosphoprotein, can sequester ERK in the cytoplasm. MEK1/2 plays a central role in integrating mitogenic signals into the ERK pathway. We tested the hypothesis that inhibition of the EGFR-ERK pathway suppresses tumorigenicity in CCC, and we investigated the role of PEA-15 in ERK-targeted therapy in CCC. We screened a panel of four CCC cell lines (RMG-I, SMOV-2, OVTOKO, and KOC-7c) and observed that the EGFR tyrosine kinase inhibitor erlotinib inhibited cell proliferation of EGFR-overexpressing CCC cell lines through partial dependence on the MEK/ERK pathway. Further, erlotinib-sensitive cell lines were also sensitive to the MEK inhibitor Selumetinib (AZD6244), which is under clinical development. Knockdown of PEA-15 expression resulted in reversal of Selumetinib-sensitive cells to resistant cells, implying that PEA-15 contributes to Selumetinib sensitivity. Both Selumetinib and erlotinib significantly suppressed tumor growth (P < 0.0001) in a CCC xenograft model. However, Selumetinib was better tolerated; erlotinib-treated mice exhibited significant toxic effects (marked weight loss, severe skin peeling) at high doses. Our findings indicate that the MEK/ERK pathway is a potential target for EGFR-overexpressing CCC and indicate that Selumetinib and erlotinib are worth exploring as therapeutic agents for CCC.

  • Abstract 3368: MEK inhibitor Selumetinib (AZD6244 – ARRY-142886) promotes mesenchymal to epithelial transition in triple-negative breast cancer
    Tumor Biology, 2011
    Co-Authors: Chandra Bartholomeusz, Ali Dadbin, Anna Kazansky, Hitomi Saso, Gabriel N. Hortobagyi
    Abstract:

    Selumetinib is a highly selective allosteric inhibitor of MEK1/2. Multiple clinical trials of Selumetinib are ongoing in patients with different types of cancer. However, the therapeutic role of Selumetinib in breast cancer has not been well defined. We sought to determine the effect of targeted inhibition of the MEK-ERK pathway by Selumetinib in triple-negative breast cancer (TNBC). We studied the effect of Selumetinib on 2 TNBC cell lines, MDA-MB-231 and SUM-149. In MDA-MB-231 cells, in 2-dimensional (2D) culture, Selumetinib at 0.1μM did not reduce cell viability, but in a 3-dimensional (3D) cell culture model, which mimics the human microenvironment, Selumetinib at 0.1 μM and 1 μM inhibited epithelial to mesenchymal transition (EMT). This result was confirmed by western blotting: expression of the mesenchymal markers fibronectin and vimentin was inhibited, and the epithelial marker beta-catenin was diffusely expressed in both the cytoplasm and the nucleus before treatment but was localized at the plasma membrane after treatment. Selumetinib in 3D cell culture also inhibited projections/filopodia formation, suggesting reversal to a more epithelial phenotype. Results were similar in SUM-149 cells: Selumetinib at 0.1 μM had minimal impact on cell viability in 2D culture, but Selumetinib at 0.1 μM and 1 μM inhibited projections/filopodia in 3D culture. Inhibition of ERK phosphorylation by Selumetinib correlated with a slight increase in the epithelial marker E-cadherin and loss of vimentin. These results suggest that treating TNBC with Selumetinib induces mesenchymal to epithelial transition (MET). In addition, in MDA-MB-231 cells, Selumetinib significantly inhibited anchorage-independent growth, an indicator of in vivo tumorigenicity. Previously, the ERK2 isoform was shown to induce EMT in epithelial cells. We therefore examined whether ERK1 and 2 expression levels correlate with Selumetinib9s effect on EMT regulation in TNBC cells. We used shRNA specifically targeting ERK1 and ERK2 (shERK1 and 2). Compared with parental MDA-MB-231 cells, stable clones that constitutively expressed shERK1 or shERK2 showed no difference in growth rate in 2D culture or projection formation in 3D culture. However, in 3D culture, treatment with Selumetinib inhibited spindle-shaped cell morphology and reduced scattering of the parental, vector-transfected, and shERK2 clones but did not inhibit mesenchymal filamentous structures in the shERK1 clones. Our data demonstrate that ERK1 may be necessary for Selumetinib -induced mesenchymal to epithelial transition in TNBC. We are planning in vivo studies to determine if low-dose Selumetinib can inhibit EMT, leading to a reduction of metastasis in a TNBC xenograft model. We will further confirm if ERK1 can serve as a biomarker for MEK inhibitor therapy in TNBC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3368. doi:10.1158/1538-7445.AM2011-3368

Paul D. Smith - One of the best experts on this subject based on the ideXlab platform.

  • dual specificity protein phosphatase dusp4 regulates response to mek inhibition in braf wild type melanoma
    British Journal of Cancer, 2020
    Co-Authors: Avinash Gupta, Paul D. Smith, Anna Schuh, Christopher Towers, Frances Willenbrock, Roz Brant, D R Hodgson, Alan Sharpe, Anthony Cutts
    Abstract:

    BACKGROUND: Aiming to improve treatment options for BRAF wild-type melanoma, we previously conducted the DOC-MEK study of docetaxel with MEK inhibitor (MEKi) Selumetinib or placebo, revealing trends to prolongation of progression-free survival (hazard ratio 0.75, P = 0.130), and improved response rates (32% vs 14%, P = 0.059) with docetaxel plus Selumetinib. NRAS status did not associate with outcome. Here, the aim was to identify novel biomarkers of response to MEKi. METHODS: A MEK 6 gene signature was quantified using NanoString and correlated with clinical outcomes. Two components of the gene signature were investigated by gene silencing in BRAF/NRAS wild-type melanoma cells. RESULTS: In melanomas of patients on the Selumetinib but not the placebo arm, two gene signature components, dual-specificity protein phosphatase 4 (DUSP4) and ETS translocation variant 4 (ETV4), were expressed more highly in responders than non-responders. In vitro, ETV4 depletion inhibited cell survival but did not influence sensitivity to MEKi Selumetinib or trametinib. In contrast, DUSP4-depleted cells showed enhanced cell survival and increased resistance to both Selumetinib and trametinib. CONCLUSIONS: ETV4 and DUSP4 associated with clinical response to docetaxel plus Selumetinib. DUSP4 depletion induced MEKi resistance, suggesting that DUSP4 is not only a biomarker but also a mediator of MEKi sensitivity. CLINICAL TRIAL REGISTRATION: DOC-MEK (EudraCT no: 2009-018153-23).

  • SELECT-4: Phase I dose escalation trial of Selumetinib (AZD6244, ARRY-142886) in combination with durvalumab (MEDI4736) in patients with advanced solid tumors.
    Journal of Clinical Oncology, 2016
    Co-Authors: Pasi A Janne, Paul D. Smith, Dana Ghiorghiu, Riccardo Belli, Phillip A. Dennis, Gabriella Mariani
    Abstract:

    TPS2607Background: Preclinical studies suggest that intermittent dosing with Selumetinib, an oral, potent and highly selective, allosteric MEK1/2 inhibitor with a short half-life, should be evaluated in combination with durvalumab, a selective, high-affinity human IgG1 mAb, that blocks PD-L1 binding to PD-1 and CD80. Selumetinib may prime the immune response and also potentially inhibit T-cell function, thereby maximizing tumor cell damage and antigen presentation during the period of MEK inhibition; intermittent dosing with Selumetinib will allow maximal relief of T-cell checkpoint blockade by durvalumab. The SELECT-4 study (NCT02586987) aims to evaluate this combination for the first time in pts. Methods: SELECT-4 is a Phase I, open-label, multicenter, dose escalation study investigating the safety and tolerability of intermittent doses of Selumetinib combined with durvalumab in pts with advanced solid tumors for which no standard therapy exists. Selumetinib (starting dose 50 mg po bid, increasing until...

  • MEK inhibitor Selumetinib (AZD6244; ARRY-142886) prevents lung metastasis in a triple-negative breast cancer xenograft model
    Molecular cancer therapeutics, 2015
    Co-Authors: Chandra Bartholomeusz, Paul D. Smith, Ali Dadbin, Hitomi Saso, Kimie Kondo, Jangsoon Lee, Xuemei Xie, Mary Kathryn Pitner, Kevin N. Dalby, Naoto T. Ueno
    Abstract:

    Patients with triple-negative breast cancer (TNBC) have a poor prognosis because TNBC often metastasizes, leading to death. Among patients with TNBC, those with extracellular signal-regulated kinase 2 (ERK2)-overexpressing tumors were at higher risk of death than those with low-ERK2-expressing tumors (hazard ratio, 2.76; 95% confidence interval, 1.19-6.41). The MAPK pathway has been shown to be a marker of breast cancer metastasis, but has not been explored as a potential therapeutic target for preventing TNBC metastasis. Interestingly, when we treated TNBC cells with the allosteric MEK inhibitor Selumetinib, cell viability was not reduced in two-dimensional culture. However, in three-dimensional culture, Selumetinib changed the mesenchymal phenotype of TNBC cells to an epithelial phenotype. Cells that undergo epithelial-mesenchymal transition (EMT) are thought to contribute to the metastatic process. EMT leads to generation of mesenchymal-like breast cancer cells with stem cell-like characteristics and a CD44(+)CD24(-/low) expression pattern. We tested the hypothesis that targeted inhibition of the MAPK pathway by Selumetinib inhibits acquisition of the breast cancer stem cell phenotype and prevents lung metastasis of TNBC. TNBC cells treated with Selumetinib showed inhibition of anchorage-independent growth, an indicator of in vivo tumorigenicity (P < 0.005), and decreases in the CD44(+)CD24(-/low) fraction, ALDH1 activity, and mammosphere-forming efficiency. Mice treated with Selumetinib formed significantly fewer lung metastases than control mice injected with vehicle (P < 0.05). Our data demonstrate that MEK inhibitors can inhibit breast cancer stem cells and may have clinical potential for the prevention of metastasis in certain cases in which tumors are MAPK dependent.

  • acute tumour response to the mek1 2 inhibitor Selumetinib azd6244 arry 142886 evaluated by non invasive diffusion weighted mri
    British Journal of Cancer, 2013
    Co-Authors: Mounia Belouechebabari, Paul D. Smith, Yann Jamin, M Revill, Jane Halliday, John C. Waterton, Vaitha Arunan, Simon Walkersamuel, Hervé Barjat
    Abstract:

    BACKGROUND: Non-invasive imaging biomarkers underpin the development of molecularly targeted anti-cancer drugs. This study evaluates tumour apparent diffusion coefficient (ADC), measured by diffusion-weighted magnetic resonance imaging (DW-MRI), as a biomarker of response to the MEK1/2 inhibitor Selumetinib (AZD6244, ARRY-142886) in human tumour xenografts. METHODS: Nude mice bearing human BRAF(V600D) WM266.4 melanoma or BRAF(V600E) Colo205 colon carcinoma xenografts were treated for 4 days with vehicle or Selumetinib. DW-MRI was performed before and 2 h after the last dose and excised tumours analysed for levels of phospho-ERK1/2, cleaved caspase 3 (CC3) and necrosis. RESULTS: Selumetinib treatment induced tumour stasis and reduced ERK1/2 phosphorylation in both WM266.4 and Colo205 tumour xenografts. Relative to day 0, mean tumour ADC was unchanged in the control groups but was significantly increased by up to 1.6-fold in Selumetinib-treated WM266.4 and Colo205 tumours. Histological analysis revealed a significant increase in necrosis in Selumetinib-treated WM266.4 and Colo205 xenografts and CC3 staining in Selumetinib-treated Colo205 tumours relative to controls. CONCLUSION: Changes in ADC following treatment with the MEK1/2 inhibitor Selumetinib in responsive human tumour xenografts were concomitant with induction of tumour cell death. ADC may provide a useful non-invasive pharmacodynamic biomarker for early clinical assessment of response to Selumetinib and other MEK-ERK1/2 signalling-targeted therapies.

  • Acute tumour response to the MEK1/2 inhibitor Selumetinib (AZD6244, ARRY-142886) evaluated by non-invasive diffusion-weighted MRI.
    British journal of cancer, 2013
    Co-Authors: Mounia Beloueche-babari, Paul D. Smith, Yann Jamin, Arunan, Simon Walker-samuel, M Revill, Jane Halliday, John C. Waterton, Hervé Barjat, Paul Workman
    Abstract:

    BACKGROUND: Non-invasive imaging biomarkers underpin the development of molecularly targeted anti-cancer drugs. This study evaluates tumour apparent diffusion coefficient (ADC), measured by diffusion-weighted magnetic resonance imaging (DW-MRI), as a biomarker of response to the MEK1/2 inhibitor Selumetinib (AZD6244, ARRY-142886) in human tumour xenografts. METHODS: Nude mice bearing human BRAF(V600D) WM266.4 melanoma or BRAF(V600E) Colo205 colon carcinoma xenografts were treated for 4 days with vehicle or Selumetinib. DW-MRI was performed before and 2 h after the last dose and excised tumours analysed for levels of phospho-ERK1/2, cleaved caspase 3 (CC3) and necrosis. RESULTS: Selumetinib treatment induced tumour stasis and reduced ERK1/2 phosphorylation in both WM266.4 and Colo205 tumour xenografts. Relative to day 0, mean tumour ADC was unchanged in the control groups but was significantly increased by up to 1.6-fold in Selumetinib-treated WM266.4 and Colo205 tumours. Histological analysis revealed a significant increase in necrosis in Selumetinib-treated WM266.4 and Colo205 xenografts and CC3 staining in Selumetinib-treated Colo205 tumours relative to controls. CONCLUSION: Changes in ADC following treatment with the MEK1/2 inhibitor Selumetinib in responsive human tumour xenografts were concomitant with induction of tumour cell death. ADC may provide a useful non-invasive pharmacodynamic biomarker for early clinical assessment of response to Selumetinib and other MEK-ERK1/2 signalling-targeted therapies.

Angela W. Dymond - One of the best experts on this subject based on the ideXlab platform.

  • Comparison of the Pharmacokinetics of the Phase II and Phase III Capsule Formulations of Selumetinib and the Effects of Food on Exposure: Results From Two Randomized Crossover Trials in Healthy Male Subjects
    Clinical therapeutics, 2017
    Co-Authors: Helen Tomkinson, Angela W. Dymond, Paul D. Martin, Mireille Cantarini, Eileen Mcbride, Eleanor Lisbon, David Holt
    Abstract:

    Abstract Purpose Selumetinib (AZD6244, ARRY-142886), an oral, potent, and highly selective mitogen-activated protein kinase 1/2 inhibitor with a short half-life, has shown activity across various tumor types. Before initiation of Phase III trials, the site, scale, and color (hypromellose shell from white [Phase II] to blue [Phase III]) of the Selumetinib 25 mg capsule manufacture was changed. We present 2 crossover trials evaluating Phase III capsules in healthy subjects. Methods The relative bioavailability trial was a Phase I, open-label, randomized, 3-treatment, 4-period, 6-sequence crossover trial in healthy male subjects (aged 18–55 years). Subjects received Selumetinib 75 mg (3 × 25 mg) Phase II or Phase III capsules, or a 35 mg oral solution, during 4 dosing periods in 1 of 6 randomized treatment sequences. The food effect trial was a Phase I, open-label, randomized, 2-period crossover trial in healthy male subjects (aged 18–45 years). Subjects were randomized to 1 of 2 sequences to receive Selumetinib 75 mg (3 × 25 mg) Phase III capsules. In sequence 1, subjects received Selumetinib after 10 hours of fasting. Following a washout period, Selumetinib was administered after a high-fat meal. In sequence 2, subjects received Selumetinib in the fed state, before the fasted state. Pharmacokinetic parameters were determined from serial blood sampling. Findings Twenty-seven subjects were randomized to the relative bioavailability trial; 26 completed all dosing periods. Mean Selumetinib AUC was unchanged (geometric least squares mean ratio [GLSMR], 90.01% [90% CI, 81.74–99.11]). Cmax was 18% lower with the Phase III capsules (GLSMR, 81.97% [90% CI, 69.01–97.36]). A post hoc exploratory statistical analysis excluding outlying observations with later Tmax showed that Phase II and III capsules produced similar exposure in terms of Cmax and AUC. High intrasubject variability for Cmax attributed to the pharmacokinetic sampling schedule was judged to have impacted on the estimated GLSMR. In the food effect trial, 34 subjects completed both study periods. A high-fat meal reduced Selumetinib Cmax compared with the fasted state (GLSMR, 49.76% [90% CI, 43.82–56.51]); AUC was minimally changed (GLSMR, 84.08% [90% CI, 80.72–87.59]). Median Tmax was prolonged by 1.49 hours. No deaths or serious adverse events were reported. Implications Selumetinib 75 mg (3 × 25 mg) Phase III capsules are being used in ongoing pivotal Phase III trials and should be administered in the fasted state. Based on findings from the relative bioavailability trial, pharmacokinetic sampling frequency was increased for healthy subject trials, including the food effect trial. ClinicalTrials.gov identifiers: NCT01635023 (relative bioavailability) and NCT01974349 (food effect).

  • pharmacokinetics of a single oral dose of the mek1 2 inhibitor Selumetinib in subjects with end stage renal disease or varying degrees of hepatic impairment compared with healthy subjects
    The Journal of Clinical Pharmacology, 2017
    Co-Authors: Angela W. Dymond, Yifan Huang, Paul Severin, Victoria Holmes, Gabriella Mariani, Paul Martin, Thomas Marbury
    Abstract:

    Two phase I open-label studies were conducted to investigate the pharmacokinetics (PK), safety, and tolerability of single oral doses of Selumetinib in subjects with end-stage renal disease (ESRD) undergoing hemodialysis and subjects with varying degrees of hepatic impairment; both studies included a matched control group comprised of healthy individuals. In the renal impairment study, subjects received single doses of Selumetinib 50 mg; those with ESRD received Selumetinib before and after dialysis (with a between-treatment washout period of ≥7 days). In the hepatic impairment study, subjects received varying single doses of Selumetinib (20-50 mg) depending on liver dysfunction (mild, moderate, or severe as per Child-Pugh classification). PK, safety, and tolerability data were collected from both studies. Overall, 24 subjects were included in the renal impairment study (ESRD, N = 12; healthy subjects, N = 12). Selumetinib exposure (AUC and Cmax ) was not increased in the ESRD group vs healthy subjects. Selumetinib exposure was lower when Selumetinib was dosed before vs after dialysis, although individual exposure was variable. Overall, 32 subjects were included in the hepatic impairment study (mild, moderate, and severe impairment, N = 8 per group; healthy subjects, N = 8). Generally, dose-normalized total Selumetinib exposure was increased by 25% to 59% in subjects with moderate and severe hepatic impairment compared with healthy subjects. Increasing Child-Pugh score, decreasing serum albumin, and increasing prothrombin time correlated with increasing unbound Selumetinib exposure. In both studies, Selumetinib was well tolerated with no new safety concerns. These studies will inform dose adjustment considerations in patients.

  • Pharmacokinetics and pharmacogenetics of the MEK1/2 inhibitor, Selumetinib, in Asian and Western healthy subjects: a pooled analysis.
    European journal of clinical pharmacology, 2017
    Co-Authors: Angela W. Dymond, David J. Carlile, Paul D. Martin, Yifan Huang, Gabriella Mariani, Cathy Elks, Susan Lovick, Ulrike Lorch, Helen Brown
    Abstract:

    Purpose Emerging data on Selumetinib, a MEK1/2 inhibitor in clinical development, suggest a possible difference in pharmacokinetics (PK) between Japanese and Western patients. This pooled analysis sought to assess the effect of ethnicity on Selumetinib exposure in healthy Western and Asian subjects, and to identify any association between genetic variants in the UGT1A1, CYP2C19 and ABCG2 genes and observed differences in Selumetinib PK.

  • effects of cytochrome p450 cyp3a4 and cyp2c19 inhibition and induction on the exposure of Selumetinib a mek1 2 inhibitor in healthy subjects results from two clinical trials
    European Journal of Clinical Pharmacology, 2017
    Co-Authors: Angela W. Dymond, Yifan Huang, Paul Severin, Paul Martin, Eleanor Lisbon, David Mathews, G Mariani
    Abstract:

    Purpose Two phase I, open-label trials in healthy subjects assessed whether co-administration with CYP3A4/CYP2C19 inhibitors, itraconazole/fluconazole (study A), or CYP3A4 inducer, rifampicin (study B), affects the exposure, safety/tolerability and pharmacokinetics of Selumetinib and its metabolite N-desmethyl Selumetinib.

  • Pharmacokinetics of a Single Oral Dose of the MEK1/2 Inhibitor Selumetinib in Subjects With End-Stage Renal Disease or Varying Degrees of Hepatic Impairment Compared With Healthy Subjects.
    Journal of clinical pharmacology, 2016
    Co-Authors: Angela W. Dymond, Paul D. Martin, Yifan Huang, Paul Severin, Victoria Holmes, Gabriella Mariani, Thomas Marbury
    Abstract:

    Two phase I open-label studies were conducted to investigate the pharmacokinetics (PK), safety, and tolerability of single oral doses of Selumetinib in subjects with end-stage renal disease (ESRD) undergoing hemodialysis and subjects with varying degrees of hepatic impairment; both studies included a matched control group comprised of healthy individuals. In the renal impairment study, subjects received single doses of Selumetinib 50 mg; those with ESRD received Selumetinib before and after dialysis (with a between-treatment washout period of ≥7 days). In the hepatic impairment study, subjects received varying single doses of Selumetinib (20-50 mg) depending on liver dysfunction (mild, moderate, or severe as per Child-Pugh classification). PK, safety, and tolerability data were collected from both studies. Overall, 24 subjects were included in the renal impairment study (ESRD, N = 12; healthy subjects, N = 12). Selumetinib exposure (AUC and Cmax ) was not increased in the ESRD group vs healthy subjects. Selumetinib exposure was lower when Selumetinib was dosed before vs after dialysis, although individual exposure was variable. Overall, 32 subjects were included in the hepatic impairment study (mild, moderate, and severe impairment, N = 8 per group; healthy subjects, N = 8). Generally, dose-normalized total Selumetinib exposure was increased by 25% to 59% in subjects with moderate and severe hepatic impairment compared with healthy subjects. Increasing Child-Pugh score, decreasing serum albumin, and increasing prothrombin time correlated with increasing unbound Selumetinib exposure. In both studies, Selumetinib was well tolerated with no new safety concerns. These studies will inform dose adjustment considerations in patients.

Hitomi Saso - One of the best experts on this subject based on the ideXlab platform.

  • MEK inhibitor Selumetinib (AZD6244; ARRY-142886) prevents lung metastasis in a triple-negative breast cancer xenograft model
    Molecular cancer therapeutics, 2015
    Co-Authors: Chandra Bartholomeusz, Paul D. Smith, Ali Dadbin, Hitomi Saso, Kimie Kondo, Jangsoon Lee, Xuemei Xie, Mary Kathryn Pitner, Kevin N. Dalby, Naoto T. Ueno
    Abstract:

    Patients with triple-negative breast cancer (TNBC) have a poor prognosis because TNBC often metastasizes, leading to death. Among patients with TNBC, those with extracellular signal-regulated kinase 2 (ERK2)-overexpressing tumors were at higher risk of death than those with low-ERK2-expressing tumors (hazard ratio, 2.76; 95% confidence interval, 1.19-6.41). The MAPK pathway has been shown to be a marker of breast cancer metastasis, but has not been explored as a potential therapeutic target for preventing TNBC metastasis. Interestingly, when we treated TNBC cells with the allosteric MEK inhibitor Selumetinib, cell viability was not reduced in two-dimensional culture. However, in three-dimensional culture, Selumetinib changed the mesenchymal phenotype of TNBC cells to an epithelial phenotype. Cells that undergo epithelial-mesenchymal transition (EMT) are thought to contribute to the metastatic process. EMT leads to generation of mesenchymal-like breast cancer cells with stem cell-like characteristics and a CD44(+)CD24(-/low) expression pattern. We tested the hypothesis that targeted inhibition of the MAPK pathway by Selumetinib inhibits acquisition of the breast cancer stem cell phenotype and prevents lung metastasis of TNBC. TNBC cells treated with Selumetinib showed inhibition of anchorage-independent growth, an indicator of in vivo tumorigenicity (P < 0.005), and decreases in the CD44(+)CD24(-/low) fraction, ALDH1 activity, and mammosphere-forming efficiency. Mice treated with Selumetinib formed significantly fewer lung metastases than control mice injected with vehicle (P < 0.05). Our data demonstrate that MEK inhibitors can inhibit breast cancer stem cells and may have clinical potential for the prevention of metastasis in certain cases in which tumors are MAPK dependent.

  • Abstract LB-362: The MEK inhibitor Selumetinib (AZD6244 - ARRY-142886) prevents lung metastasis in a triple-negative breast cancer (TNBC) xenograft model
    Experimental and Molecular Therapeutics, 2012
    Co-Authors: Chandra Bartholomeusz, Paul D. Smith, Hitomi Saso, Gabriel N. Hortobagyi, Kimie Kondo, Dadbin Ali, Naoto T. Ueno
    Abstract:

    Patients with TNBC are negative for estrogen receptor, progesterone receptor, and HER2 expression, and have a very poor prognoses because tumors often metastasize, leading to death. Preventing metastasis as well as inhibiting the tumor growth, is crucial to improving the prognosis of TNBC. We previously showed that patients with ERK2-overexpressing TNBC were at higher risk of death than those with low-ERK2-expressing tumors. Interestingly, when we treated the TNBC cells lines MDA-MB-231 and SUM-149 with the MEK1/2 ATP uncompetitive kinase inhibitor (Selumetinib) at concentrations of 0.1 and 1.0 μM, it did not reduce cell viability in a two-dimensional (2D) cell culture. However, in a three-dimensional (3D) cell culture model, Selumetinib changed the mesenchymal phenotype of TNBC to an epithelial phenotype. Cells undergoing epithelial-mesenchymal transition are well known to potentially contribute to the metastatic process and have increased ability to form mammospheres. Thus, we hypothesized that targeted inhibition of the MEK-ERK pathway by Selumetinib may prevent lung metastasis in TNBC. In the present study, we observed that SUM-149 cells treated with Selumetinib (0.1, 1.0 μM) exhibited cell-cycle arrest at G1 but did not exhibit apoptosis indicated by an increased proportion of cells at sub-G1 phase. Both SUM-149 and MDA-MB-231 cells treated with Selumetinib exhibited significant inhibition of anchorage-independent growth, an indicator of in vivo tumorigenicity (P Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-362. doi:1538-7445.AM2012-LB-362

  • mek1 2 inhibitor Selumetinib azd6244 inhibits growth of ovarian clear cell carcinoma in a pea 15 dependent manner in a mouse xenograft model
    Molecular Cancer Therapeutics, 2012
    Co-Authors: Chandra Bartholomeusz, Anna Kazansky, Hitomi Saso, Tetsuro Oishi, Ugur Akar, Ping Liu, Kimie Kondo, Savitri Krishnamurthy, J S Lee
    Abstract:

    Clear cell carcinoma (CCC) of the ovary tends to show resistance to standard chemotherapy, which results in poor survival for patients with CCC. Developing a novel therapeutic strategy is imperative to improve patient prognosis. Epidermal growth factor receptor (EGFR) is frequently expressed in epithelial ovarian cancer. One of the major downstream targets of the EGFR signaling cascade is ERK. PEA-15, a 15-kDa phosphoprotein, can sequester ERK in the cytoplasm. MEK1/2 plays a central role in integrating mitogenic signals into the ERK pathway. We tested the hypothesis that inhibition of the EGFR-ERK pathway suppresses tumorigenicity in CCC, and we investigated the role of PEA-15 in ERK-targeted therapy in CCC. We screened a panel of four CCC cell lines (RMG-I, SMOV-2, OVTOKO, and KOC-7c) and observed that the EGFR tyrosine kinase inhibitor erlotinib inhibited cell proliferation of EGFR-overexpressing CCC cell lines through partial dependence on the MEK/ERK pathway. Further, erlotinib-sensitive cell lines were also sensitive to the MEK inhibitor Selumetinib (AZD6244), which is under clinical development. Knockdown of PEA-15 expression resulted in reversal of Selumetinib-sensitive cells to resistant cells, implying that PEA-15 contributes to Selumetinib sensitivity. Both Selumetinib and erlotinib significantly suppressed tumor growth (P < 0.0001) in a CCC xenograft model. However, Selumetinib was better tolerated; erlotinib-treated mice exhibited significant toxic effects (marked weight loss, severe skin peeling) at high doses. Our findings indicate that the MEK/ERK pathway is a potential target for EGFR-overexpressing CCC and indicate that Selumetinib and erlotinib are worth exploring as therapeutic agents for CCC.

  • MEK1/2 Inhibitor Selumetinib (AZD6244) Inhibits Growth of Ovarian Clear Cell Carcinoma in a PEA-15-dependent Manner in a Mouse Xenograft Model
    Molecular cancer therapeutics, 2011
    Co-Authors: Chandra Bartholomeusz, Anna Kazansky, Hitomi Saso, Tetsuro Oishi, Ugur Akar, Ping Liu, Kimie Kondo, Savitri Krishnamurthy, Jangsoon Lee, Francisco J. Esteva
    Abstract:

    Clear cell carcinoma (CCC) of the ovary tends to show resistance to standard chemotherapy, which results in poor survival for patients with CCC. Developing a novel therapeutic strategy is imperative to improve patient prognosis. Epidermal growth factor receptor (EGFR) is frequently expressed in epithelial ovarian cancer. One of the major downstream targets of the EGFR signaling cascade is ERK. PEA-15, a 15-kDa phosphoprotein, can sequester ERK in the cytoplasm. MEK1/2 plays a central role in integrating mitogenic signals into the ERK pathway. We tested the hypothesis that inhibition of the EGFR-ERK pathway suppresses tumorigenicity in CCC, and we investigated the role of PEA-15 in ERK-targeted therapy in CCC. We screened a panel of four CCC cell lines (RMG-I, SMOV-2, OVTOKO, and KOC-7c) and observed that the EGFR tyrosine kinase inhibitor erlotinib inhibited cell proliferation of EGFR-overexpressing CCC cell lines through partial dependence on the MEK/ERK pathway. Further, erlotinib-sensitive cell lines were also sensitive to the MEK inhibitor Selumetinib (AZD6244), which is under clinical development. Knockdown of PEA-15 expression resulted in reversal of Selumetinib-sensitive cells to resistant cells, implying that PEA-15 contributes to Selumetinib sensitivity. Both Selumetinib and erlotinib significantly suppressed tumor growth (P < 0.0001) in a CCC xenograft model. However, Selumetinib was better tolerated; erlotinib-treated mice exhibited significant toxic effects (marked weight loss, severe skin peeling) at high doses. Our findings indicate that the MEK/ERK pathway is a potential target for EGFR-overexpressing CCC and indicate that Selumetinib and erlotinib are worth exploring as therapeutic agents for CCC.

  • Abstract 3368: MEK inhibitor Selumetinib (AZD6244 – ARRY-142886) promotes mesenchymal to epithelial transition in triple-negative breast cancer
    Tumor Biology, 2011
    Co-Authors: Chandra Bartholomeusz, Ali Dadbin, Anna Kazansky, Hitomi Saso, Gabriel N. Hortobagyi
    Abstract:

    Selumetinib is a highly selective allosteric inhibitor of MEK1/2. Multiple clinical trials of Selumetinib are ongoing in patients with different types of cancer. However, the therapeutic role of Selumetinib in breast cancer has not been well defined. We sought to determine the effect of targeted inhibition of the MEK-ERK pathway by Selumetinib in triple-negative breast cancer (TNBC). We studied the effect of Selumetinib on 2 TNBC cell lines, MDA-MB-231 and SUM-149. In MDA-MB-231 cells, in 2-dimensional (2D) culture, Selumetinib at 0.1μM did not reduce cell viability, but in a 3-dimensional (3D) cell culture model, which mimics the human microenvironment, Selumetinib at 0.1 μM and 1 μM inhibited epithelial to mesenchymal transition (EMT). This result was confirmed by western blotting: expression of the mesenchymal markers fibronectin and vimentin was inhibited, and the epithelial marker beta-catenin was diffusely expressed in both the cytoplasm and the nucleus before treatment but was localized at the plasma membrane after treatment. Selumetinib in 3D cell culture also inhibited projections/filopodia formation, suggesting reversal to a more epithelial phenotype. Results were similar in SUM-149 cells: Selumetinib at 0.1 μM had minimal impact on cell viability in 2D culture, but Selumetinib at 0.1 μM and 1 μM inhibited projections/filopodia in 3D culture. Inhibition of ERK phosphorylation by Selumetinib correlated with a slight increase in the epithelial marker E-cadherin and loss of vimentin. These results suggest that treating TNBC with Selumetinib induces mesenchymal to epithelial transition (MET). In addition, in MDA-MB-231 cells, Selumetinib significantly inhibited anchorage-independent growth, an indicator of in vivo tumorigenicity. Previously, the ERK2 isoform was shown to induce EMT in epithelial cells. We therefore examined whether ERK1 and 2 expression levels correlate with Selumetinib9s effect on EMT regulation in TNBC cells. We used shRNA specifically targeting ERK1 and ERK2 (shERK1 and 2). Compared with parental MDA-MB-231 cells, stable clones that constitutively expressed shERK1 or shERK2 showed no difference in growth rate in 2D culture or projection formation in 3D culture. However, in 3D culture, treatment with Selumetinib inhibited spindle-shaped cell morphology and reduced scattering of the parental, vector-transfected, and shERK2 clones but did not inhibit mesenchymal filamentous structures in the shERK1 clones. Our data demonstrate that ERK1 may be necessary for Selumetinib -induced mesenchymal to epithelial transition in TNBC. We are planning in vivo studies to determine if low-dose Selumetinib can inhibit EMT, leading to a reduction of metastasis in a TNBC xenograft model. We will further confirm if ERK1 can serve as a biomarker for MEK inhibitor therapy in TNBC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3368. doi:10.1158/1538-7445.AM2011-3368

Mireille Cantarini - One of the best experts on this subject based on the ideXlab platform.

  • abstract ct034 osimertinib plus Selumetinib for patients pts withegfr mutant egfrm nsclc following disease progression on an egfr tki results from the phase ib tatton study
    Cancer Research, 2019
    Co-Authors: Suresh S Ramalingam, Hideo Saka, Myung-ju Ahn, Mireille Cantarini, Geoffrey R. Oxnard, Leora Horn, Toyoaki Hida, Remy B Verheijen, Jonathan Wessen, Yuichiro Ohe
    Abstract:

    The EGFR T790M mutation is the most common cause of resistance in pts receiving a first or second-generation EGFR-TKI for EGFRm NSCLC. Other resistance mechanisms include upregulation of the RAS/RAF/MEK/ERK signaling pathway. The Phase Ib TATTON study (NCT02143466) assessed osimertinib in combination with novel therapeutics including the oral, potent and selective MEK1/2 inhibitor, Selumetinib (AZD6244, ARRY-142886). Here we present data from the dose-finding (Part A) and dose expansion (Part B) portions of this study. Adults with advanced EGFRm NSCLC and disease progression on prior EGFR-TKI, including third-generation agents, were eligible regardless of T790M or KRAS status. In Part A, pts received osimertinib 80 mg QD plus intermittent or continuous Selumetinib. Asian pts received continuous Selumetinib 25/50 mg BID, while other pts received continuous Selumetinib 50/75 mg BID, or intermittent Selumetinib 75 mg BID 4 days on/3 days off (4/3), or on days 1 and 4 of each week of treatment. In Part B, pts received osimertinib plus intermittent Selumetinib 75 mg BID 4/3. Primary objectives were safety, tolerability and preliminary efficacy (objective response rate [ORR]). Secondary objectives included duration of response (DoR) and pharmacokinetics (PK). At data cut-off (Feb 2018), 36 and 47 pts received treatment in Parts A and B, respectively. In Part A, most pts were white (18, 50%) or Asian (17, 47%), and 26 (72%) had a baseline exon 19 deletion. In Part B, 44 (94%) pts were Asian, and 30 (64%) had a baseline exon 19 deletion. The most common treatment-related adverse events (TRAEs) in Part A were diarrhea (27, 75%), nausea (14, 39%) and fatigue (12, 33%). Six pts had dose-limiting toxicities (DLTs) with continuous Selumetinib (all Grade 3): ALT and AST increase (50 mg); diarrhea, asthenia and dizziness (50 mg); diarrhea (n=2, 75 mg); diarrhea and nausea (75 mg); and pneumonitis (75 mg). No DLTs were reported with intermittent dosing, so the Selumetinib 4/3 schedule was selected for Part B. The most common TRAEs in Part B were diarrhea (38, 81%), stomatitis (15, 32%), and paronychia (14, 30%). In Part A, 15 (42%) pts had confirmed partial response (PR); 14 (39%) had stable disease at 6 weeks (SD); 3 (8%) had progressive disease (PD); 2 (6%) died; and 2 (6%) were not evaluable (NE). Median DoR was 16.6 months; 77% remained in response at 12 months. In Part B, 16 (34%) pts had confirmed PR; 16 (34%) had SD; 11 (23%) had PD; 2 (4%) died; and 2 (4%) were NE. Median DoR was 9.1 months; 31% remained in response at 12 months. Osimertinib and Selumetinib PK parameters were similar to those previously observed with monotherapy. Osimertinib plus intermittent Selumetinib had an acceptable safety profile and demonstrated preliminary anti-tumor activity in pts with disease progression on a prior EGFR-TKI. Responses were durable and this combination warrants further investigation. Citation Format: Suresh S. Ramalingam, Hideo Saka, Myung-Ju Ahn, Helena Yu, Helena Yu, Leora Horn, Toyoaki Hida, Mireille Cantarini, Remy Verheijen, Jonathan Wessen, Geoffrey Oxnard, Yuichiro Ohe. Osimertinib plus Selumetinib for patients (pts) with EGFR-mutant (EGFRm) NSCLC following disease progression on an EGFR-TKI: Results from the Phase Ib TATTON study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT034.

  • Comparison of the Pharmacokinetics of the Phase II and Phase III Capsule Formulations of Selumetinib and the Effects of Food on Exposure: Results From Two Randomized Crossover Trials in Healthy Male Subjects
    Clinical therapeutics, 2017
    Co-Authors: Helen Tomkinson, Angela W. Dymond, Paul D. Martin, Mireille Cantarini, Eileen Mcbride, Eleanor Lisbon, David Holt
    Abstract:

    Abstract Purpose Selumetinib (AZD6244, ARRY-142886), an oral, potent, and highly selective mitogen-activated protein kinase 1/2 inhibitor with a short half-life, has shown activity across various tumor types. Before initiation of Phase III trials, the site, scale, and color (hypromellose shell from white [Phase II] to blue [Phase III]) of the Selumetinib 25 mg capsule manufacture was changed. We present 2 crossover trials evaluating Phase III capsules in healthy subjects. Methods The relative bioavailability trial was a Phase I, open-label, randomized, 3-treatment, 4-period, 6-sequence crossover trial in healthy male subjects (aged 18–55 years). Subjects received Selumetinib 75 mg (3 × 25 mg) Phase II or Phase III capsules, or a 35 mg oral solution, during 4 dosing periods in 1 of 6 randomized treatment sequences. The food effect trial was a Phase I, open-label, randomized, 2-period crossover trial in healthy male subjects (aged 18–45 years). Subjects were randomized to 1 of 2 sequences to receive Selumetinib 75 mg (3 × 25 mg) Phase III capsules. In sequence 1, subjects received Selumetinib after 10 hours of fasting. Following a washout period, Selumetinib was administered after a high-fat meal. In sequence 2, subjects received Selumetinib in the fed state, before the fasted state. Pharmacokinetic parameters were determined from serial blood sampling. Findings Twenty-seven subjects were randomized to the relative bioavailability trial; 26 completed all dosing periods. Mean Selumetinib AUC was unchanged (geometric least squares mean ratio [GLSMR], 90.01% [90% CI, 81.74–99.11]). Cmax was 18% lower with the Phase III capsules (GLSMR, 81.97% [90% CI, 69.01–97.36]). A post hoc exploratory statistical analysis excluding outlying observations with later Tmax showed that Phase II and III capsules produced similar exposure in terms of Cmax and AUC. High intrasubject variability for Cmax attributed to the pharmacokinetic sampling schedule was judged to have impacted on the estimated GLSMR. In the food effect trial, 34 subjects completed both study periods. A high-fat meal reduced Selumetinib Cmax compared with the fasted state (GLSMR, 49.76% [90% CI, 43.82–56.51]); AUC was minimally changed (GLSMR, 84.08% [90% CI, 80.72–87.59]). Median Tmax was prolonged by 1.49 hours. No deaths or serious adverse events were reported. Implications Selumetinib 75 mg (3 × 25 mg) Phase III capsules are being used in ongoing pivotal Phase III trials and should be administered in the fasted state. Based on findings from the relative bioavailability trial, pharmacokinetic sampling frequency was increased for healthy subject trials, including the food effect trial. ClinicalTrials.gov identifiers: NCT01635023 (relative bioavailability) and NCT01974349 (food effect).

  • Selumetinib plus dacarbazine versus placebo plus dacarbazine as first-line treatment for BRAF-mutant metastatic melanoma: a phase 2 double-blind randomised study.
    The Lancet. Oncology, 2013
    Co-Authors: Caroline Robert, Kevin B. Kim, Paul Lorigan, Reinhard Dummer, Ralf Gutzmer, Marta Nyakas, Ana Arance, Gabriella Liszkay, Dirk Schadendorf, Mireille Cantarini
    Abstract:

    Summary Background Patients with metastatic melanoma, 50% of whose tumours harbour a BRAF mutation, have a poor prognosis. Selumetinib, a MEK1/2 inhibitor, has shown antitumour activity in patients with BRAF -mutant melanoma and in preclinical models when combined with chemotherapy. This study was designed to look for a signal of improved efficacy by comparing the combination of Selumetinib and dacarbazine with dacarbazine alone. Methods This double-blind, randomised, placebo-controlled phase 2 study investigated Selumetinib plus dacarbazine versus placebo plus dacarbazine as first-line treatment in patients older than 18 years with histologically or cytologically confirmed advanced BRAF -mutant cutaneous or unknown primary melanoma. Patients were randomly assigned by central interactive voice response system (1:1 ratio, block size four) to take either oral Selumetinib (75 mg twice daily in a 21-day cycle) or placebo; all patients received intravenous dacarbazine (1000 mg/m 2 on day 1 of a 21-day cycle). Patients, investigators, and the study team were masked to the treatment assigned. The primary endpoint was overall survival analysed by intention to treat. This study is registered at ClinicalTrials.gov, NCT00936221. Findings Between July 20, 2009, and April 8, 2010, 91 patients were randomly assigned to receive dacarbazine in combination with Selumetinib (n=45) or placebo (n=46). Overall survival did not differ significantly between groups (median 13·9 months, 80% CI 10·2–15·6, in the Selumetinib plus dacarbazine group and 10·5 months, 9·6–14·7, in the placebo plus dacarbazine group; hazard ratio [HR] 0·93, 80% CI 0·67–1·28, one-sided p=0·39). However, progression-free survival was significantly improved in the Selumetinib plus dacarbazine group versus the placebo plus dacarbazine group (HR 0·63, 80% CI 0·47–0·84, one-sided p=0·021), with a median of 5·6 months (80% CI 4·9–5·9) versus 3·0 months (2·8–4·6), respectively. The most frequent adverse events included nausea (28 [64%] of 44 patients on Selumetinib vs 25 [56%] of 45 on placebo), acneiform dermatitis (23 [52%] vs one [2%]), diarrhoea (21 [48%] vs 13 [29%]), vomiting (21 [48%] vs 15 [33%]), and peripheral oedema (19 [43%] vs three [7%]). The most common grade 3–4 adverse event was neutropenia (six [14%] patients in the Selumetinib plus dacarbazine group vs four [9%] in the placebo plus dacarbazine group). Interpretation Selumetinib plus dacarbazine showed clinical activity in patients with BRAF -mutant cutaneous or unknown primary melanoma, reflected by a significant benefit in progression-free survival compared with placebo plus dacarbazine group, although no significant change in overall survival was noted. The tolerability of this combination was generally consistent with monotherapy safety profiles. Funding AstraZeneca.

  • phase ii open label randomized trial of the mek1 2 inhibitor Selumetinib as monotherapy versus temozolomide in patients with advanced melanoma
    Clinical Cancer Research, 2012
    Co-Authors: John M. Kirkwood, Jeffrey A Sosman, Lars Bastholt, Caroline Robert, James Larkin, Peter Hersey, Mark R. Middleton, Mireille Cantarini, Victoria Zazulina, Karin Kemsley
    Abstract:

    Purpose: To compare the efficacy and tolerability of the mitogen-activated protein (MAP)/extracellular signal-regulated (ERK) kinase (MEK) 1/2 inhibitor Selumetinib versus temozolomide in chemotherapy-naive patients with unresectable stage III/IV melanoma. Experimental Design: This phase II, open-label, multicenter, randomized, parallel-group study examined the effect of 100 mg oral Selumetinib twice daily in 28-day cycles versus oral temozolomide (200 mg/m 2 /d for 5 days, then 23 days off-treatment). The primary endpoint was progression-free survival. Results: Two hundred patients were randomized. Progression-free survival did not differ significantly between Selumetinib and temozolomide (median time to event 78 and 80 days, respectively; hazard ratio, 1.07; 80% confidence interval, 0.86–1.32). Objective response was observed in six (5.8%) patients receiving Selumetinib and nine (9.4%) patients in the temozolomide group. Among patients with BRAF mutations, objective responses were similar between Selumetinib and temozolomide groups (11.1% and 10.7%, respectively). However, five of the six Selumetinib partial responders were BRAF mutated. Frequently reported adverse events with Selumetinib were dermatitis acneiform (papular pustular rash; 59.6%), diarrhea (56.6%), nausea (50.5%), and peripheral edema (40.4%), whereas nausea (64.2%), constipation (47.4%), and vomiting (44.2%) were reported with temozolomide. Conclusions: No significant difference in progression-free survival was observed between patients with unresectable stage III/IV melanoma unselected for BRAF / NRAS mutations, who received therapy with Selumetinib or temozolomide. Five of six patients with partial response to Selumetinib had BRAF mutant tumors. Clin Cancer Res; 18(2); 555–67. ©2011 AACR .

  • Phase II, Open-Label, Randomized Trial of the MEK1/2 Inhibitor Selumetinib as Monotherapy versus Temozolomide in Patients with Advanced Melanoma
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2011
    Co-Authors: John M. Kirkwood, Jeffrey A Sosman, Lars Bastholt, Caroline Robert, James Larkin, Peter Hersey, Mark R. Middleton, Mireille Cantarini, Victoria Zazulina, Karin Kemsley
    Abstract:

    Purpose: To compare the efficacy and tolerability of the mitogen-activated protein (MAP)/extracellular signal-regulated (ERK) kinase (MEK) 1/2 inhibitor Selumetinib versus temozolomide in chemotherapy-naive patients with unresectable stage III/IV melanoma. Experimental Design: This phase II, open-label, multicenter, randomized, parallel-group study examined the effect of 100 mg oral Selumetinib twice daily in 28-day cycles versus oral temozolomide (200 mg/m 2 /d for 5 days, then 23 days off-treatment). The primary endpoint was progression-free survival. Results: Two hundred patients were randomized. Progression-free survival did not differ significantly between Selumetinib and temozolomide (median time to event 78 and 80 days, respectively; hazard ratio, 1.07; 80% confidence interval, 0.86–1.32). Objective response was observed in six (5.8%) patients receiving Selumetinib and nine (9.4%) patients in the temozolomide group. Among patients with BRAF mutations, objective responses were similar between Selumetinib and temozolomide groups (11.1% and 10.7%, respectively). However, five of the six Selumetinib partial responders were BRAF mutated. Frequently reported adverse events with Selumetinib were dermatitis acneiform (papular pustular rash; 59.6%), diarrhea (56.6%), nausea (50.5%), and peripheral edema (40.4%), whereas nausea (64.2%), constipation (47.4%), and vomiting (44.2%) were reported with temozolomide. Conclusions: No significant difference in progression-free survival was observed between patients with unresectable stage III/IV melanoma unselected for BRAF / NRAS mutations, who received therapy with Selumetinib or temozolomide. Five of six patients with partial response to Selumetinib had BRAF mutant tumors. Clin Cancer Res; 18(2); 555–67. ©2011 AACR .