azd-6244 and Neoplasm-Metastasis

Melanoma is the fifth most common cancer in men and seventh most common in women in the USA, and prognosis for patients with advanced melanoma is poor. The mitogen-activated protein (MAP) kinase signaling pathway is essential for proliferation and survival of melanoma cells. Effective inhibition of MAP kinase kinase (MEK) protein has been shown to downregulate the MAP kinase pathway, resulting in melanoma cell growth arrest and apoptosis. Selumetinib is an orally available, selective non-ATP-competitive MEK1 and MEK2 inhibitor.. In this review, the authors discuss the rationale for MEK inhibition therapy in melanoma and summarize data from the preclinical and clinical studies of selumetinib for advanced melanoma.. As a majority of advanced melanomas have an activated MAP kinase signal transduction pathway, there is a strong preclinical rationale for investigating selumetinib in patients with metastatic melanoma. The results of early clinical studies of selumetinib suggest that selumetinib may have a role in melanoma therapy, especially in certain subsets of patients, such as those whose tumor harbors a BRAF mutation. Current studies of selumetinib are addressing the efficacy of selumetinib in these patients.

Topics: Animals; Benzimidazoles; Clinical Trials as Topic; Drug Evaluation, Preclinical; Humans; Melanoma; Mitogen-Activated Protein Kinase Kinases; Neoplasm Metastasis; Randomized Controlled Trials as Topic; Signal Transduction

Thyroid cancer is the most common endocrine malignancy. Some advanced disease is, or becomes, resistant to radioactive iodine therapy (refractory disease); this holds poor prognosis of 10% 10-year overall survival. Whilst Sorafenib and Lenvatinib are now licenced for the treatment of progressive iodine refractory thyroid cancer, these treatments require continuing treatment and can be associated with significant toxicity. Evidence from a pilot study has demonstrated feasibility of Selumetinib to allow the reintroduction of I-131 therapy; this larger, multicentre study is required to demonstrate the broader clinical impact of this approach before progression to a confirmatory trial.. SEL-I-METRY is a UK, single-arm, multi-centre, two-stage phase II trial. Participants with locally advanced or metastatic differentiated thyroid cancer with at least one measureable lesion and iodine refractory disease will be recruited from eight NHS Hospitals and treated with four-weeks of oral Selumetinib and assessed for sufficient I-123 uptake (defined as any uptake in a lesion with no previous uptake or 30% or greater increase in uptake). Those with sufficient uptake will be treated with I-131 and followed for clinical outcomes. Radiation absorbed doses will be predicted from I-123 SPECT/CT and verified from scans following the therapy. Sixty patients will be recruited to assess the primary objective of whether the treatment schedule leads to increased progression-free survival compared to historical control data.. The SEL-I-METRY trial will investigate the effect of Selumetinib followed by I-131 therapy on progression-free survival in radioiodine refractory patients with differentiated thyroid cancer showing increased radioiodine uptake following initial treatment with Selumetinib. In addition, information on toxicity and dosimetry will be collected. This study presents an unprecedented opportunity to investigate the role of lesional dosimetry in molecular radiotherapy, leading to greater personalisation of therapy. To date this has been a neglected area of research. The findings of this trial will be useful to healthcare professionals and patients alike to determine whether further study of this agent is warranted. It is hoped that the development of the infrastructure to deliver a multicentre trial involving molecular radiotherapy dosimetry will lead to further trials in this field.. SEL-I-METRY is registered under ISRCTN17468602 , 02/12/2015.

Topics: Antineoplastic Agents; Benzimidazoles; Clinical Trials, Phase II as Topic; Humans; Iodine Radioisotopes; Molecular Targeted Therapy; Multicenter Studies as Topic; Neoplasm Metastasis; Phenylurea Compounds; Quinolines; Sorafenib; Thyroid Neoplasms; United Kingdom

Activation of the RAS/RAF/MEK/ERK pathway may confer resistance to chemotherapy in non-small cell lung cancer (NSCLC). Selumetinib (AZD6244, ARRY142886), a MEK1/2 inhibitor combined with chemotherapy in patients with NSCLC was evaluated in two schedules to evaluate efficacy and toxicity.. IND.219 was a three-arm study of first line pemetrexed/platinum chemotherapy with two schedules of selumetinib (Arm A: intermittent given on days 2-19; Arm B: continuous given on days 1-21) versus chemotherapy alone (Arm C). The primary endpoint was objective response rate (ORR); secondary objectives were tolerability, progression-free survival (PFS), overall survival (OS). The trial was stopped at the planned interim analysis.. Arms A/B/C enrolled 20/21/21 patients, ORR was 35% (95% CI 15-59% median duration 3.8 months), 62% (95% CI 38-82%; median duration 6.3 months), 24% (95% CI 8-47%; median duration 11.6 months) respectively. The PFS (months Arm A, B, C) was 7.5, 6.7, 4.0 respectively (hazard ratio (HR) PFS Arm A over Arm C: 0.76 [95% CI, 0.38-1.51, 2-sided p = 0.42]; Arm B over Arm C 0.75 [95% CI 0.37-1.54, p = 0.43]. Skin and gastrointestinal adverse events were more common with the addition of selumetinib. A high incidence of venous thromboembolism was seen in all arms.. Selumetinib combined with chemotherapy was associated with a higher response rate. Continuous selumetinib appeared to be superior to an intermittent schedule. PFS was prolonged with the addition of selumetinib, however this was not statistically significant.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Canada; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Pemetrexed; Platinum Compounds; Proto-Oncogene Proteins p21(ras); Survival Analysis

Purpose Uveal melanoma is the most common primary intraocular malignancy in adults with no effective systemic treatment option in the metastatic setting. Selumetinib (AZD6244, ARRY-142886) is an oral, potent, and selective MEK1/2 inhibitor with a short half-life, which demonstrated single-agent activity in patients with metastatic uveal melanoma in a randomized phase II trial. Methods The Selumetinib (AZD6244: ARRY-142886) (Hyd-Sulfate) in Metastatic Uveal Melanoma (SUMIT) study was a phase III, double-blind trial ( ClinicalTrial.gov identifier: NCT01974752) in which patients with metastatic uveal melanoma and no prior systemic therapy were randomly assigned (3:1) to selumetinib (75 mg twice daily) plus dacarbazine (1,000 mg/m

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Dacarbazine; Double-Blind Method; Female; Humans; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Placebos; Progression-Free Survival; Uveal Neoplasms

Combination of selumetinib plus docetaxel provided clinical benefit in a previous phase II trial for patients with KRAS-mutant advanced non-small-cell lung cancer (NSCLC). The phase II SELECT-2 trial investigated safety and efficacy of selumetinib plus docetaxel for patients with advanced or metastatic NSCLC.. Patients who had disease progression after first-line anti-cancer therapy were randomized (2 : 2 : 1) to selumetinib 75 mg b.i.d. plus docetaxel 60 or 75 mg/m2 (SEL + DOC 60; SEL + DOC 75), or placebo plus docetaxel 75 mg/m2 (PBO + DOC 75). Patients were initially enrolled independently of KRAS mutation status, but the protocol was amended to include only patients with centrally confirmed KRAS wild-type NSCLC. Primary end point was progression-free survival (PFS; RECIST 1.1); statistical analyses compared each selumetinib group with PBO + DOC 75 for KRAS wild-type and overall (KRAS mutant or wild-type) populations.. A total of 212 patients were randomized; 69% were KRAS wild-type. There were no statistically significant improvements in PFS or overall survival for overall or KRAS wild-type populations in either selumetinib group compared with PBO + DOC 75. Overall population median PFS for SEL + DOC 60, SEL + DOC 75 compared with PBO + DOC 75 was 3.0, 4.2, and 4.3 months, HRs: 1.12 (90% CI: 0.8, 1.61) and 0.92 (90% CI: 0.65, 1.31), respectively. In the overall population, a higher objective response rate (ORR; investigator assessed) was observed for SEL + DOC 75 (33%) compared with PBO + DOC 75 (14%); odds ratio: 3.26 (90% CI: 1.47, 7.95). Overall the tolerability profile of SEL + DOC was consistent with historical data, without new or unexpected safety concerns identified.. The primary end point (PFS) was not met. The higher ORR with SEL + DOC 75 did not translate into prolonged PFS for the overall or KRAS wild-type patient populations. No clinical benefit was observed with SEL + DOC in KRAS wild-type patients compared with docetaxel alone. No unexpected safety concerns were reported.. Clinicaltrials.gov NCT01750281.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Docetaxel; Double-Blind Method; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Proto-Oncogene Proteins p21(ras); Taxoids

Oncogenic KRAS mutations represent the largest genomically defined subset of lung cancer, and are associated with activation of the RAS/RAF/MEK/ERK pathway. There are currently no therapies specifically approved for patients with KRAS-mutant (KRASm) non-small-cell lung cancer (NSCLC), and these patients derive less clinical benefit from chemotherapy than the overall NSCLC population. In a recent phase II study, selumetinib (AZD6244, ARRY-142886), an oral, potent and selective, allosteric MEK1/2 inhibitor with a short half-life, combined with docetaxel, improved clinical outcome as second-line treatment for patients with KRASm NSCLC. This combination will be further evaluated in the phase III SELECT-1 study.. SELECT-1 (NCT01933932) is a randomized, double-blind, placebo-controlled phase III study assessing the efficacy and safety of selumetinib plus docetaxel in patients with KRASm locally advanced or metastatic NSCLC, eligible for second-line treatment. The primary endpoint is progression-free survival (PFS); secondary endpoints include overall survival, objective response rate, duration of response, and safety and tolerability. Approximately 634 patients will be randomized 1:1 to receive selumetinib (75 mg twice daily on a continuous oral administration schedule) in combination with docetaxel (75 mg/m(2), intravenously on day 1 of every 21-day cycle) or placebo in combination with docetaxel (same schedule), until objective disease progression. Patients may continue to receive treatment after objective disease progression if deemed appropriate by the investigator.. If the primary endpoint of PFS is met, selumetinib plus docetaxel would be the first targeted treatment for patients with KRASm advanced NSCLC who are eligible for second-line treatment.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carcinoma, Non-Small-Cell Lung; Docetaxel; Double-Blind Method; Female; Humans; Male; Middle Aged; Mutation; Neoplasm Metastasis; Neoplasm Staging; Placebos; Proto-Oncogene Proteins p21(ras); Research Design; Taxoids; Treatment Outcome; Young Adult

Combined treatment with cisplatin and gemcitabine (CisGem) is the standard of care for patients with advanced biliary tract cancer (ABC). Selumetinib (AZD6244, ARRY-142886) potently and selectively inhibits MEK1/2, an intracellular kinase and has shown activity in ABC. The objective of the ABC-04 trial was to establish the recommended dose of selumetinib in combination with CisGem in patients with ABC.. Eligible patients were ≥ 18 years, had histologically or cytologically-confirmed unresectable recurrent or metastatic biliary tract, gallbladder or ampullary carcinoma, WHO performance status 0-2, and adequate major organ function. Patients may have had prior surgery, radiotherapy or adjuvant chemotherapy, but no prior CisGem and no prior chemotherapy for locally advanced or metastatic disease. Patients received cisplatin 25 mg/m(2) plus gemcitabine 1000 mg/m(2) intravenously on days 1 and 8 of a 21-day cycle. Selumetinib capsules were taken daily. Patients received up to 8 cycles of CisGem and could receive selumetinib until disease progression. A dose de-escalation scheme was used to determine the recommended dose of selumetinib. The first dose level was 75 mg bd. Patients were recruited in cohorts of 3 and assessed for dose limiting toxicity (DLT) during the first cycle of treatment.. Thirteen patients were recruited, of whom 12 were evaluable for DLT (1 did not start treatment). All evaluable patients received the starting dose of selumetinib 75 mg bd and one patient experienced a DLT (cardiac chest pain). The median number of days selumetinib was taken (adjusted for the number of days of dose interruptions) was 171.5 (IQR: 75.5 to 344). Two patients remained on treatment at 14 and 19 months post registration. There were 3 temporary and 1 permanent interruptions of selumetinib in cycle 1. Eight patients were evaluable for objective response (RECIST v1.1): 3 had a partial response and 5 stable disease. The median PFS was 6.4 months (IQR 5.2 to 13.7). Toxicities related to selumetinib were mostly related to oedema and rash, grade 1-2 and manageable. Pharmacokinetic analysis showed that the AUC(0-t), AUC(0-∞) and Cmax of selumetinib increased by 12, 11 and 30 % respectively when it was administered with CisGem, while Cmax for the N-desmethyl metabolite of selumetinib decreased by 40 %. There was no evidence that the time of Cmax for selumetinib or N-desmethyl metabolite of selumetinib were different when selumetinib was administered alone or with CisGem.. The recommended dose of selumetinib when combined with CisGem was 75 mg bd. Translational studies are underway to identify biomarkers that may predict outcome (ClinicalTrials.gov identifier: NCT01242605 July 6(th) 2010).

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Biliary Tract Neoplasms; Cause of Death; Cisplatin; Combined Modality Therapy; Deoxycytidine; Female; Gemcitabine; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Neoplasm Staging; Retreatment; Treatment Outcome

Uveal melanoma is characterised by mutations in GNAQ and GNA11, resulting in Ras/Raf/MEK/ERK pathway activation. Treatment with selumetinib (AZD6244, ARRY-142886), a MEK1/2 inhibitor, results in antitumour effects in uveal melanoma pre-clinical models. A randomised phase II trial demonstrated improved progression-free survival (PFS) and response rate (RR) with selumetinib monotherapy versus chemotherapy with temozolomide or dacarbazine in patients with metastatic uveal melanoma. Pre-clinically, selumetinib in combination with alkylating agents enhanced antitumour activity compared with chemotherapy alone. We hypothesise that selumetinib in combination with dacarbazine will result in improved clinical outcomes in patients with metastatic uveal melanoma versus dacarbazine alone.. SUMIT is a randomised, international, double-blind, placebo-controlled, phase III study assessing the efficacy and safety of selumetinib in combination with dacarbazine in patients with metastatic uveal melanoma who have not received prior systemic therapy. Primary endpoint is PFS. Secondary endpoints include objective RR, duration of response, change in tumour size at Week 6, overall survival, safety and tolerability. Exploratory endpoints include efficacy in tumours with GNAQ or GNA11 mutations. Eligible patients must have: ≥1 lesion that can be accurately measured at baseline, and is suitable for accurate repeated measurements; ECOG performance status 0-1; life expectancy>12 weeks. Mutation status for GNAQ/GNA11 will be assessed retrospectively. An estimated 128 patients from approximately 50 sites globally will be randomised (3:1) to selumetinib 75 mg twice daily or placebo in combination with dacarbazine 1000 mg/m(2) on Day 1 of every 21-day cycle until objective disease progression, intolerable toxicity or occurrence of another discontinuation criterion. Randomisation will be stratified by the presence/absence of liver metastases. Tumours will be evaluated by RECIST v1.1 every 6 weeks. All patients have the option of receiving selumetinib with or without dacarbazine at disease progression. Study enrolment began in April 2014 and is expected to complete in early 2015.. Treatment of patients with metastatic uveal melanoma represents an area of high unmet medical need. This study evaluating selumetinib in combination with dacarbazine was designed with input from the US FDA, and is the first potential registration trial to be conducted in patients with metastatic uveal melanoma.. Clinicaltrials.gov (Date of registration, October 10, 2013) REGISTRATION NUMBER: NCT01974752 Trial abbreviation: SUMIT.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Dacarbazine; Disease-Free Survival; Female; Humans; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Uveal Neoplasms

Metastatic thyroid cancers that are refractory to radioiodine (iodine-131) are associated with a poor prognosis. In mouse models of thyroid cancer, selective mitogen-activated protein kinase (MAPK) pathway antagonists increase the expression of the sodium-iodide symporter and uptake of iodine. Their effects in humans are not known.. We conducted a study to determine whether the MAPK kinase (MEK) 1 and MEK2 inhibitor selumetinib (AZD6244, ARRY-142886) could reverse refractoriness to radioiodine in patients with metastatic thyroid cancer. After stimulation with thyrotropin alfa, dosimetry with iodine-124 positron-emission tomography (PET) was performed before and 4 weeks after treatment with selumetinib (75 mg twice daily). If the second iodine-124 PET study indicated that a dose of iodine-131 of 2000 cGy or more could be delivered to the metastatic lesion or lesions, therapeutic radioiodine was administered while the patient was receiving selumetinib.. Of 24 patients screened for the study, 20 could be evaluated. The median age was 61 years (range, 44 to 77), and 11 patients were men. Nine patients had tumors with BRAF mutations, and 5 patients had tumors with mutations of NRAS. Selumetinib increased the uptake of iodine-124 in 12 of the 20 patients (4 of 9 patients with BRAF mutations and 5 of 5 patients with NRAS mutations). Eight of these 12 patients reached the dosimetry threshold for radioiodine therapy, including all 5 patients with NRAS mutations. Of the 8 patients treated with radioiodine, 5 had confirmed partial responses and 3 had stable disease; all patients had decreases in serum thyroglobulin levels (mean reduction, 89%). No toxic effects of grade 3 or higher attributable by the investigators to selumetinib were observed. One patient received a diagnosis of myelodysplastic syndrome more than 51 weeks after radioiodine treatment, with progression to acute leukemia.. Selumetinib produces clinically meaningful increases in iodine uptake and retention in a subgroup of patients with thyroid cancer that is refractory to radioiodine; the effectiveness may be greater in patients with RAS-mutant disease. (Funded by the American Thyroid Association and others; ClinicalTrials.gov number, NCT00970359.).

Topics: Adult; Aged; Benzimidazoles; Female; Humans; Iodine Radioisotopes; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Middle Aged; Mitogen-Activated Protein Kinases; Multimodal Imaging; Mutation; Neoplasm Metastasis; Positron-Emission Tomography; Radiometry; Symporters; Thyroid Neoplasms; Thyrotropin Alfa; Tomography, X-Ray Computed

Biliary cancers (BCs) carry a poor prognosis, but targeting the RAS/RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-related kinase (ERK) pathway is of significance. Selumetinib is an inhibitor of MEK1/2, so this trial was designed to determine the safety and efficacy of selumetinib in BC.. This was a multi-institutional phase II study of selumetinib at 100 mg given orally twice per day to patients with advanced BC. The primary end point was response rate. All patients were required to provide tissue before enrolling. The levels of phosphorylated ERK (pERK) and AKT (pAKT) were assessed by immunohistochemistry. Tumors were genotyped for the presence of BRAF- and/or RAS-activating mutations.. Twenty-eight eligible patients with a median age of 55.6 years were enrolled. Thirty-nine percent of patients had received one prior systemic therapy. Three patients (12%) had a confirmed objective response. Another 17 patients (68%) experienced stable disease (SD), 14 of whom (56%) experienced prolonged SD (> 16 weeks). Patients gained an average nonfluid weight of 8.6 pounds. Median progression-free survival was 3.7 months (95% CI, 3.5 to 4.9) and median overall survival was 9.8 months (95% CI, 5.97 to not available). Toxicities were mild, with rash (90%) and xerostomia (54%) being most frequent. Only one patient experienced grade 4 toxicity (fatigue). All patients had tissue available for analysis. No BRAF V600E mutations were found. Two patients with short-lived SD had KRAS mutations. Absence of pERK staining was associated with lack of response.. Selumetinib displays interesting activity and acceptable tolerability in patients with metastatic BC. Our results warrant further evaluation of selumetinib in patients with metastatic BC.

Topics: Adult; Aged; Benzimidazoles; Biliary Tract Neoplasms; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Middle Aged; Mutation; Neoplasm Metastasis; Phosphorylation; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins p21(ras); ras Proteins

Topics: Acrylonitrile; Aged; Aniline Compounds; Barrett Esophagus; Benzimidazoles; Drug Therapy, Combination; Endoscopy, Digestive System; Female; Humans; Liver; Liver Neoplasms; Magnetic Resonance Imaging; Melanoma; Mutation; Neoplasm Metastasis; Paclitaxel; Prognosis; Stomach; Tomography, X-Ray Computed; Tubulin Modulators; Uveal Neoplasms

Pancreatic cancer is a lethal disease and its prognosis remains dismal. The modest results of existing available treatments in the second line setting reveal the need of new therapeutic strategies. In this year's American Society of Clinical Oncology (ASCO) Annual Meeting two remarkable trials and one retrospective analysis were presented regarding this vulnerable group of patients. According to the published results, docetaxel plus oxaliplatin (Abstract #4034), selumetinib plus erlotinib (Abstract #4014) and nab-paclitaxel (Abstract #e15057) have shown promising efficacy and manageable toxicity that should be elucidated and confirmed by new prospective, large, randomized trials.

Topics: Adenocarcinoma; Albumins; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Docetaxel; Erlotinib Hydrochloride; Humans; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Quinazolines; Taxoids; Treatment Outcome

Compared with temozolomide chemotherapy, the MEK inhibitor selumetinib extended progression-free survival by nearly 9 weeks in patients with melanoma of the eye participating in a phase II trial, making it the first effective drug for the rare disease.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Clinical Trials, Phase II as Topic; Dacarbazine; Disease-Free Survival; Eye Neoplasms; Humans; Melanoma; Neoplasm Metastasis; Temozolomide; Uveal Neoplasms